Compound

ABSTRACT

The invention provides compounds of formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein X is O or S; 
             R 1  is H, OH, SH, nitro, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , halo, haloC 1-6 alkyl, CN, C 1-6 -alkyl, OC 1-6 alkyl, C 1-6 alkylCOOH, C 1-6 alkylCOOC 1-6 alkyl, C 2-6 -alkenyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkylC 6-10 aryl, heterocyclyl, heteroaryl, CONH 2 , CONHC 1-6 alkyl, CON(C 1-6 alkyl) 2 , OCOC 1-6 alkyl, or is an acidic group, such as a group comprising a carboxyl, phosphate, phosphinate, sulfate, sulfonate, or tetrazolyl group; 
             R 2  is as defined for R 1  or R 1  and R 2  taken together can form a 6-membered aromatic ring optionally substituted by up to 4 groups R 5 ; 
             R 3  is H, halo (preferably fluoro), or CHal 3  (preferably CF 3 ), 
             each R 5  is defined as for R 1 ; 
             V 1  is a covalent bond or a C 1-20 alkyl group, or C 2-20 -mono or multiply unsaturated alkenyl group; said alkyl or alkenyl groups being optionally interupted by one or more heteroatoms selected from O, NH, N(C 1-6  alkyl), S, SO, or SO 2 ; 
             M 1  is absent or is a C 5-10  cyclic group or a C 5-15  aromatic group; and 
             R 4  is H, halo, OH, CN, nitro, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , haloC 1-6 alkyl, a C 1-20 alkyl group, or C 2-20 -mono or multiply unsaturated alkenyl group, said C 1-20 alkyl or C 2-20 alkenyl groups being optionally interupted by one or more heteroatoms selected from O, NH, N(C 1-6  alkyl), S, SO, or SO 2 ; 
             with the proviso that the group V 1 M 1 R 4  as a whole provides at least 4 backbone atoms from the C(R 3 ) group; 
             or a salt, ester, solvate, N-oxide, or prodrug thereof; for use in the treatment of a chronic inflammatory condition.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the following U.S. ProvisionalApplication No. 61/248,338, filed Oct. 2, 2009, the entire contents ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to the use of various 2-oxothiazole or2-oxooxazole compounds for use in the prevention or treatment of chronicinflammatory disorders such as glomerulonephritis, rheumatoid arthritisand psoriasis. The invention also relates to certain new 2-oxothiazoleor 2-oxo-oxazole compounds, pharmaceutical compositions comprising saidcompounds and to new processes for the manufacture thereof.

Mammalian cells contain a large number of phospholipases that hydrolysephospholipids in a structurally specific manner for production of amyriad of products, many of which have potent biological activity. Therehas been considerable interest in characterising these enzymes becauseof their role in production of lipid mediators of inflammation. Sincethe first studies 20 years ago showing that mammalian cells contain acystolic calcium dependent phospholipase specific for arachidonic acid,an extensive amount of evidence has substantiated a primary role forcPLA₂ as the key enzyme that mediates the release of arachidonic acidfor the production of eicosanoids.

The enzyme cPLA₂ contributes to the pathogenesis of a variety ofdiseases particularly those in which inflammation plays a primary roleimplicating a role for inflammatory lipid mediators in diseasepathogenesis. The inhibition therefore of such lipase enzymes offers apotential therapy for inflammatory conditions in particular chronicinflammatory conditions such as those above, psoriasis andglomerulonephritis.

The phospholipases are a group of enzymes that release unsaturated fattyacids from the sn2 position of membrane phospholipids. Once released,the fatty acids are converted by various enzymes into biologically veryimportant signalling molecules. Release of arachidonate initiates thearachidonate cascade leading to the synthesis of eicosanoids such asprostaglandins.

Eicosanoids are important in a variety of physiological processes andplay a central role in inflammation. In Inflammation, Vol. 18, No. 11994, Andersen et al identify the presence of certain phospholipases inpsoriatic human skin.

It is therefore believed that inhibition of phospholipase enzymes shouldhave potential in curing some of the inflammatory symptoms, includingepidermal hyperproliferation due to increased leukotriene production,related to eicosanoid production and cell activation in both epidermisand dermis in psoriasis.

Psoriasis is a common, chronic, inflammatory skin disorder. Psoriatictissue is characterised by chronic inflammation in both epidermis anddermis, the disease being further characterised by hyperplasia ofepidermal keratinocytes, fibroblast activation, alteration of eicosanoidmetabolism, and leukocyte infiltration.

Glomerulonephritis, also known as glomerular nephritis, abbreviated GN,is a renal disease characterized by inflammation of the glomeruli, orsmall blood vessels in the kidneys. It may present with isolatedhematuria and/or proteinuria or as a nephrotic syndrome, acute renalfailure, or chronic renal failure. Glomerulonephritis is categorisedinto several different pathological patterns, which are broadly groupedinto non-proliferative or proliferative types.

The glomerulus is a unique vascular network with three specialised typesof cell: the endothelial cell, the mesangial cell and the visceralepithelial cell

Mesangial cells (MC) serve a number of functions in the renal glomerularcapillary including structural support of the capillary tuft, modulationof the glomerular hemodynamics and a phagocytic function allowingremoval of macromolecules and immune complexes. The proliferation of MCis a prominent feature of glomerular disease including IgA nephropathy,membranoproliferative glomerulonephritis, lupus nephritis, and diabeticnephropathy.

Reduction of MC proliferation in glomerular disease models by treatmentwith, for example, a low protein diet has been shown to produceextracellular matrix expansion and glomerulosclerotic changes. MCproliferation inhibitors may therefore offer therapeutic opportunitiesfor the treatment of proliferative glomerular disease.

Mesangial proliferative glomerulonephritis is a form ofglomerulonephritis which involves inflammation at the kidney glomeruli.The mesangial cells which are a part of the glomerular capillariesincrease in size giving the glomeruli a lumpy appearance. The disorderusually causes nephritic syndrome which represents protein loss in theurine. It may be present as acute, chronic or rapidly progressiveglomerulonephritis and may progress to chronic renal failure.

The present inventors seek new treatments for, inter alia, chronicinflammatory conditions such as GN and psoriasis.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that certain2-oxo-thiazoles or 2-oxo-oxazoles are ideal cPLA₂ inhibitors and offernew therapeutic routes to the treatment of chronic inflammatorydisorders.

2-oxothiazole type structures are not new. In Bioorganic and MedicinalChemistry 16 (2008) 1562-1595, there is a review of chemistry in thisfield. 2-oxo (benz)thiazoles carrying peptides or amino acids on the2-position (i.e. where the 2-oxo group forms part of the backbone of anamino acid) are known in the art as thrombin inhibitors.

Also reported are certain hydrolase and transferase inhibitors inparticular having a 2-oxo-oleyl side chain. Similar compounds as fattyacid amide hydrolase inhibitors are reported in J Med Chem. Vol. 51, No.237329-7343. Their potential as inhibitors of cPLA₂ is not discussed.

A wider variety of 2-oxo-oxazole compounds are known from these papers.The majority of these compounds are either unsubstituted oxazole ringsor they carry substituents in the position adjacent the oxygen atom.Their potential as inhibitors of cPLA₂ is not discussed.

Never before therefore, have the compounds claimed herein beenidentified as potential inhibitors of phospholipase enzymes and hence nolink with chronic inflammatory conditions has been made.

Thus, viewed from one aspect the invention provides a compound offormula (I)

wherein X is O or S;

R₁ is H, OH, SH, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, halo,haloC₁₋₆alkyl, CN, C₁₋₆-alkyl, OC₁₋₆alkyl, C₂₋₆-alkenyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, C₁₋₆alkylC₆₋₁₀aryl, heterocyclyl,heteroaryl, CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, OCOC₁₋₆alkyl,C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl or is an acidic group, such as agroup comprising a carboxyl, phosphate, phosphinate, sulfate, sulfonate,or tetrazolyl group;

R₂ is as defined for R₁ or R₁ and R₂ taken together can form a6-membered aromatic ring optionally substituted by up to 4 groups R₅;

R₃ is H, halo (preferably fluoro), or CHal₃ (preferably CF₃),

each R₅ is defined as for R₁;

V₁ is a covalent bond or a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiplyunsaturated alkenyl group; said alkyl or alkenyl groups being optionallyinterupted by one or more heteroatoms selected from O, NH, N(C₁₋₆alkyl), S, SO, or SO₂;

M₁ is absent or is a C₅₋₁₀ cyclic group or a C₅₋₁₅ aromatic group (e.g.C₆₋₁₄ aromatic group); and

R₄ is H, halo, OH, CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,haloC₁₋₆alkyl, a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturatedalkenyl group, said C₁₋₂₀alkyl or C₂₋₂₀alkenyl groups being optionallyinterupted by one or more heteroatoms selected from O, NH, N(C₁₋₆alkyl), S, SO, or SO₂;

with the proviso that the group V₁M₁R₄ as a whole provides at least 4backbone atoms from the C(R₃) group;

or a salt, ester, solvate, N-oxide, or prodrug thereof;

for use in the treatment of a chronic inflammatory condition.

Viewed from another aspect the invention provides a compound of formula(II)

wherein R₁, R₂, R₃, R₅ and R₄M₁V₁ are as hereinbefore defined;

or a salt, ester, solvate, N-oxide, or prodrug thereof;

with the proviso that R₄M₁V₁C(R₃) is not oleyl.

Viewed from another aspect the invention provides a compound of formula(III)

wherein R₆ is H, C₁₋₆alkyl, COOH, COOC₁₋₆alkyl, CONH₂, CONHC₁₋₆alkyl,CON(C₁₋₆alkyl)₂, C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl;

R₇ is H;

wherein R₃ is as hereinbefore defined;

V₁ is a covalent bond or a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiplyunsaturated alkenyl group;

M₁ is a covalent bond or is a C₅₋₁₀ cyclic group or a C₅₋₁₀ aromaticgroup; and

R₄ is H, halo, OH, CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,haloC₁₋₆alkyl, a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturatedalkenyl group, said alkyl or alkenyl groups being optionally interuptedby one or more heteroatoms selected from O, NH, N(C₁₋₆ alkyl), S, SO, orSO₂;

or a salt, ester, solvate, N-oxide, or prodrug thereof

with the proviso that R₄M₁V₁C(R₃) is not oleyl or —(CH₂)₆Ph.

Viewed from another aspect the invention provides a compound of formula(I′)

wherein X is O or S;

R₁ is H, OH, SH, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, halo,haloC₁₋₆alkyl, CN, C₁₋₆-alkyl, OC₁₋₆alkyl, C₂₋₆-alkenyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, C₁₋₆alkylC₆₋₁₀aryl, heterocyclyl,heteroaryl, CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, OCOC₁₋₆alkyl,C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl or is an acidic group, such as agroup comprising a carboxyl, phosphate, phosphinate, sulfate, sulfonate,or tetrazolyl group;

R₂ is as defined for R₁ or R₁ and R₂ taken together can form a6-membered aromatic ring optionally substituted by up to 4 groups R₅;

each R_(3′) is the same or different and is H, C₁₋₆alkylCOOR_(a) whereR_(a) is H or C₁₋₆ alkyl, halo (preferably fluoro), or CHal₃ (preferablyCF₃),

each R₅ is defined as for R₁;

V_(1′) is a covalent bond, —NHCOC₀₋₆alkyl- (i.e. where NH is adjacentthe CR_(3′) group), a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiplyunsaturated alkenyl group; said alkyl or alkenyl groups being optionallyinterupted by one or more heteroatoms selected from O, NH, N(C₁₋₆alkyl), S, SO, or SO₂;

M₁ is absent or is a C₅₋₁₀ cyclic group or a C₅₋₁₅ aromatic group (e.g.C₆₋₁₄ aromatic group); and

R₄ is H, halo, OH, CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,haloC₁₋₆alkyl, a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturatedalkenyl group, said C₁₋₂₀alkyl or C₂₋₂₀alkenyl groups being optionallyinterupted by one or more heteroatoms selected from O, NH, N(C₁₋₆alkyl), S, SO, or SO₂;

with the proviso that the group V_(1′)M₁R₄ as a whole provides at least4 backbone atoms from the C(R_(3′))₂ group;

or a salt, ester, solvate, N-oxide, or prodrug thereof

with the proviso that R₄M₁V₁C(R_(3′))₂ is not oleyl. It is alsopreferred if R₄M₁V₁C(R_(3′))₂ is not CH₂Ph.

The invention also concerns a compound of formula (I′) as hereinbeforedefined but without the disclaimer for use in the treatment of a chronicinflammatory condition.

Viewed from another aspect the invention provides a compound of formula(III′)

wherein R₆, R₇, R_(3′), V_(1′), M₁, R₄ are as hereinbefore defined; withthe proviso that R₄M₁V₁C(R₃) is not oleyl or —(CH₂)₆Ph.

Viewed from another aspect the invention provides a pharmaceuticalcomposition claim comprising a compound of formula (I′), (II), (III) or(III′) as hereinbefore defined.

Viewed from another aspect the invention provides a compound of formula(I′), (II), (III) or (III′) as hereinbefore defined for use in therapy.

Viewed from another aspect the invention provides use of the a compoundof formula (I) or (I′) as hereinbefore defined in the manufacture of amedicament for the treatment of a chronic inflammatory condition.

Viewed from another aspect the invention provides a method of treating achronically inflammatory disorder comprising administering to a patientan effective amount of a compound of formula (I) or (I′) as hereinbeforedefined.

DEFINITIONS

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl radicals and may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl.

The term “cycloalkyl” refers to an optionally substituted carbocyclecontaining no heteroatoms, including mono-, and multicyclic saturatedcarbocycles, as well as fused ring systems. Cycloalkyl includes suchfused ring systems as spirofused ring systems. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “alkenyl” includes both straight and branched chain alkenylradicals. The term alkenyl refers to an alkenyl radicals one or moredouble bonds and may be, but is not limited to vinyl, allyl, propenyl,i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl andhexenyl.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturatedaromatic ring. Examples and suitable values of the term “aryl” arephenyl, naphtyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and thelike.

In this specification, unless stated otherwise, the term “heteroaryl”refers to an optionally substituted monocyclic or bicyclic unsaturated,aromatic ring system containing at least one heteroatom selectedindependently from N, O or S. Examples of “heteroaryl” may be, but arenot limited to thiophene, thienyl, pyridyl, thiazolyl, isothiazolyl,furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl,isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyland thiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl,tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl,thionaphtyl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrazinyl,pyrimidinyl, quinolyl, phtalazinyl, naphthyridinyl, quinoxalinyl,quinazolyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyridyl,imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, cynnolyl,pteridinyl, furazanyl, benzotriazolyl, pyrazolopyridinyl, purinyl andthe like.

In this specification, unless stated otherwise, the term “heterocycle”refers to an optionally substituted, monocyclic or bicyclic saturated,partially saturated or unsaturated ring system containing at least oneheteroatom selected independently from N, O and S, e.g. piperidinyl,morpholino, or piperazinyl.

Any cyclic group can be a cycloalkyl group, cycloalkenyl group orheterocyclic group.

Any aromatic group can be aryl or heteroaryl in nature, e.g. phenyl,naphthyl or pyridyl.

An acidic group is one comprising a carboxyl, phosphate, phosphinate,sulfate, sulfonate, or tetrazolyl group, e.g. an C₁₋₆alkyl linked to acarboxyl, phosphate, phosphinate, sulfate, sulfonate, or tetrazolylgroup. Highly preferred acidic groups are COOH, COOC₁₋₆alkyl, orC₁₋₆alkyl substituted by COOH, COOC₁₋₆alkyl or C₆₋₁₀aryl groupsubstituted by COOH, COOC₁₋₆alkyl.

DETAILED DESCRIPTION OF INVENTION

It is preferred if X is S and the ring system is a thiazole system.

It is preferred if R₁ is hydrogen.

It is preferred if R₂ is hydrogen or is an acidic group, e.g. a groupcomprising a carboxylic group or derivative thereof (i.e. a COO group).Thus, R₂ may be COOH, or an ester, e.g. alkyl ester thereof. The acidgroup may also be spaced apart from the ring by some form of linkingchain such as an alkylene chain or an aromatic group. Highly preferredgroups are COOH, COOC₁₋₆alkyl and C₁₋₆alkylCOOH.

It is believed that the presence of a carboxyl functional group attachedto the heterocyclic ring enhances interaction of the compound with theactive site of the phospholipase enzyme, in particular, the side chainof arginine 200. This arginine is believed to carry a free guanidinegroup so any substituent which can favourably interact with thisguanidine is preferred at the R₁ and/or R₂ position.

In one embodiment R₁ and R₂ can be taken together to form a ring systemsuch as a phenyl ring or pyridine ring. Where a pyridine ring systemforms the N atom is preferably in the 4-position of the ring (S=1position, N=3, N=4). Preferably the ring system will be a carbon ringsystem, e.g. forming a benzothiazole type structure. If such a ringsystem is formed, it may be substituted preferably by 1 or 2 groups R₅.Preferences for R₅ are the same as those for R₂. Preferably the R₅ groupis positioned on the 5-position of the ring (where S is the 1-positionand N is the 3-position). Ideally however such a ring system isunsubstituted.

Preferred compounds in this regard are of formula (VII)

where the substituents are as hereinbefore defined and Z is C or N.

It is especially preferred if at least one of R₁ and R₂ (especially R₁)is hydrogen. The heterocyclic ring is ideally only monosubstituted. In afurther preferred embodiment both R₁ and R₂ are hydrogen.

R₃ is preferably hydrogen or, in a highly preferred embodiment, R₃ ishalo, especially fluoro. It is believed that the presence of the F atomadjacent the carbonyl enhances the activity of the carbonyl group andmay also interact favourably with the active site in the cPLA₂ enzyme,in particular IVa PLA₂.

It is preferred if one R_(3′) is H. It is also preferable if one R_(3′)is halo, especially fluoro. The presence of two fluoro atoms as R_(3′)is also preferred. It is believed that the presence of the F atomadjacent the carbonyl enhances the activity of the carbonyl group andmay also interact favourably with the active site in the cPLA₂ enzyme,in particular IVa PLA₂.

The discussion of the group V₁M₁R₄ which follows also applies to V₁M₁R₄.The group V₁M₁R₄ as a whole provides at least 4 backbone atoms from theC(R₃) group. Preferably, V₁M₁R₄ provides at least 5 backbone atoms, morepreferably at least 7 backbone atoms especially at least 10 backboneatoms from the C(R₃) group. For the avoidance of doubt, where there isan aromatic group in the backbone, the backbone is considered to followthe shortest route around the ring. Thus, for a 1,4-phenyl group, thatwould constitute 4 backbone atoms. A 1,3 linked 5 membered ring in thebackbone would constitute 3 backbone atoms and so on.

V₁ (or V_(1′)) is preferably an C₁₋₁₅-alkyl group, C₂₋₂₀-alkenyl groupor is a —C₁₋₆alkylO-group (i.e. where the O atom bonds to M₁). Anyalkenyl group can have one or more than one double bond. Where more thanone double bond is present, it is preferred if these are non conjugated.Double bonds will preferably take the cis form. Preferred alkyl groupsfor V₁ (or V_(1′)) include C₁₋₆-alkyl.

It is especially preferred if any alkyl or alkenyl group in V₁ (orV_(1′)) is linear.

V_(1′) may also represent an amide linkage NHCO which may thenoptionally carry an alkyl chain of up to 6 carbon atoms. That chain ispreferably linear. The NH part of the linkage is adjacent the CR_(3′)group.

Preferably M₁ is either absent or is an C₆₋₁₀aryl group, especially aphenyl group. Alternatively, M₁ may be a bicyclic aromatic group such asdecalin. A further preferred embodiment is where M₁ represents abiphenyl group, i.e. a C₅₋₁₅ aromatic group in which two phenyl groupsare directly linked. Where M₁ is a phenyl group, V₁ or V_(1′) and R₄ arepreferably attached in the 1 and 4 positions of the ring, i.e. they arepara to each other.

R₄ is preferably an H atom, C₁₋₁₀alkyl group or an C₁₋₁₀alkoxy group.

In one embodiment it is preferred in any compound of the invention thatR₄M₁V₁C(R₃) or R₄M₁V_(1′)C(R_(3′))₂ is not oleyl or —(CH₂)₆Ph.

Thus, a still more preferred compound of the invention is of formula(VI)

wherein R₁ is H;

R₂ is H, COOH, COOC₁₋₆alkyl, C₁₋₆alkylCOOH, or C₁₋₆alkylCOOC₁₋₆alkyl;

R₃ is H or F;

V₁ is C₁₋₁₅-alkyl group, C₂₋₂₀-alkenyl group or is a —C₁₋₆-alkylO-group;

M₁ is absent or is a phenyl group;

R₄ is H, C₁₋₁₀alkyl group or an C₁₋₁₀alkoxy group.

In further highly preferred combinations:

1. V₁ is C₁₋₁₅-alkyl group or C₂₋₂₀-alkenyl group, M₁ is absent and R₄is H.2. V₁ is C₁₋₆-alkyl group or is a —C₁₋₆-alkylO group, M₁ is a phenylgroup, and R₄ is H or C₁₋₆ alkoxy (where the O atom is adjacent the M₁group);3. R₄V₁M₁ represents a C₁₀₋₂₀ linear alkyl group.

Also preferred are options 1-3 above in which V₁ is V_(1′)

In a highly preferred embodiment, the invention provides the compoundsin the examples.

Synthesis

The manufacture of the compounds of the invention typically involvesknown literature reactions. For example, the formation of an2-oxothiazole, the precursor to many of the claimed compounds, can beachieved by reaction of an aldehyde XCOH with thiazole in the presenceof a base and subsequent oxidation of the hydroxyl to a ketone. The Xgroup is obviously selected to form the desired R₄M₁V₁ or R₄M₁V_(1′)group or a precursor thereof.

These reactions are summarised in Scheme 1 below.

It will be appreciated that in the scheme above and many of those below,specific reagents and solvents may mentioned to aid the skilled man incarrying out the reactions described. The skilled man will appreciatehowever that a variety of different conditions, reagents, solvents,reactions etc could be used to effect the chemistry described and theconditions quoted are not intended to be limiting on the reactionsdescribed.

An alternative strategy involves the reaction of an alkoxy amideXCON(Oalkyl) with thiazole in base which affords 2-oxothiazolesdirectly. This reaction is summarised in scheme 2.

The inventors have however found a new and preferred way of forming2-oxothiazoles and this forms a still yet further aspect of theinvention. The new process involves the reaction of an oxo-morpholinostructure with thiazole, typically in the presence of a base. Thisreaction affords 2-oxo thiazoles directly and is a new reaction.

Thus viewed from another aspect the invention provides a process for theformation of a 2oxothiazole comprising reacting a compound of formula(IV)

wherein Y is an organic group, e.g. a group R₄M₁V₁CH(R₃),

with an optionally substituted thiazole in the presence of a base so asto form an optionally substituted compound of formula (V)

This reaction is effected in the presence of a base, e.g. nBuLi or thelike. Ideally, the reaction is effected at low temperature, e.g. at 0°C. or below so in an ice bath, or other known cooling system, e.g.liquid ammonia.

It will be appreciated that this reaction is preferably used to formcompounds of formula (I) or (II) or (III) or their (I′)/(III′) analoguesand this forms a still further aspect of the invention. It will bepreferred therefore if the definition if Y reflects the groupR₄M₁V₁CH(R₃) or R₄M₁V₁C(R₃)₂ or forms a precursor thereto. It will alsobe preferred if the thiazole used reflects the preferred thiazolereactant required to make a compound of the invention, i.e. carrying thenecessary R₁/R₂ substituents etc. The reaction is however more generallyapplicable so variable Y is broadly defined and the thiazole may beoptionally substituted.

It is believed that the morpholino intermediates used in this reactionare new and these form a further aspect of the invention. Thus, viewedfrom another aspect the invention provides an intermediate compound offormula (IX)

wherein R₄M₁V₁CH(R₃) is as hereinbefore defined.

Viewed from another aspect the invention provides an intermediatecompound of formula (IX′)

wherein R₄M₁V₁C(R₃)₂ is as hereinbefore defined.

There are still further ways of developing a 2-oxo thiazole ringcarrying a substituent. The ring itself can be generated from athioamide as described in scheme 3.

As noted above, an interesting class of compounds of the invention arethose having a fluoro atom adjacent the carbonyl. This is convenientlyintroduced before attachment of the ring system by conventionalchemistry. A hydroxy group may be converted to a fluoro group usingDiethylaminosulfur trifluoride (DAST) for example. This chemistry iselucidated below:

The formed compound can react with thiazole as described above.Variations of the substituents on the heterocyclic rings andmanipulation of the side chain binding the carbonyl can be achievedusing all manner of synthetic techniques which the skilled man willknow. Guidance is offered in the examples as to how to make a widevariety of compounds and the principles described can be extended to thecompounds encompassed by the claims.

The principles described above for preparing thiazoles can be extendedto the oxazole species.

Intermediates

Various intermediates are also new and form a further aspect of theinvention. In particular, the invention covers the reduced analogue ofthe final 2-oxoheterocycle, i.e. a 2-hydroxy analogue. Thus, viewed fromanother aspect the invention provides a compound of formula (VIII)

wherein R₁, R₂, R₃, R_(3′), R₅ and R₄M₁V₁/R₄M₁V_(1′) are as hereinbeforedefined;

or a salt, ester, solvate, N-oxide, or prodrug thereof;

preferably with the proviso that R₄M₁V₁C(R₃) or R₄M₁V₁C(R₃)₂ is notoleyl.

Chronic Inflammatory Disorders

The compounds of the invention are used in the treatment of chronicinflammatory disorders, in particular those associated withphospholipase inhibition.

Preferably, any compound of the invention will achieve 90% inhibitionagainst IVa PLA₂.

Preferably, compounds of the invention inhibit IVa cPLA₂ at a low μMrange such as 5 μM or less, preferably 4 μM or less.

It is further preferred that the compounds of the invention show greaterinhibition of IVa cPLA₂ than iPLA₂ or sPLA₂ according to publishedassays for these enzymes (see, for example, Yang, H et al. (1999) Anal.Biochem. 269: 278). Ideally, the compounds of the invention show limitedor no inhibition of iPLA₂ or sPLA₂ and they are therefore highlyspecific for the IVa cPLA₂ enzyme.

Specific diseases of interest are glomerulonephritis, inflammatorydermatoses such as psoriasis and rheumatoid arthritis.

Further conditions of interest include other inflammatory dermatosessuch as atopic dermatitis, allergic contact dermatitis, seborrheicdermatitis, pityriasis rosea, lichen planus and drug eruptions.

Furthermore the compounds of the invention may have use in the treatmentof other types of arthritis and dermatoses, inflammatory CNS diseases,multiple sclerosis, chronic obstructive pulmonary disease, chronic lunginflammatory conditions, inflammatory bowel disease such as ulcerativecolitis and crohns disease and cardiovascular disease.

Thus viewed from a further aspect the invention provides for thetreatment of any of the conditions listed above using the compounds ofthe invention.

Formulation

The compounds of the invention are preferably formulated aspharmaceutically acceptable compositions. The phrase “pharmaceuticallyacceptable”, as used in connection with compositions of the invention,refers to molecular entities and other ingredients of such compositionsthat are physiologically tolerable and do not typically produce untowardreactions when administered to a mammal (e.g. human). Preferably, asused herein, the term “pharmaceutically acceptable” means approved by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein mammals, and more particularly in humans.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound is administered. Such pharmaceutical carriers can besterile liquids, such as water, saline solutions, aqueous dextrosesolutions, aqueous glycerol solutions, and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Suitablepharmaceutical carriers are described in “Remington's PharmaceuticalSciences” by E. W. Martin, 18th Edition, incorporated by reference.Particularly preferred for the present invention are carriers suitablefor immediate-release, i.e., release of most or all of the activeingredient over a short period of time, such as 60 minutes or less, andmake rapid absorption of the drug possible.

The compounds of the invention can be administered in salt, solvate,prodrug or ester form, especially salt form. Typically, a pharmaceuticalacceptable salt may be readily prepared by using a desired acid. Thesalt may precipitate from solution and be collected by filtration or maybe recovered by evaporation of the solvent. For example, an aqueoussolution of an acid such as hydrochloric acid may be added to an aqueoussuspension of a compound of formula (I) and the resulting mixtureevaporated to dryness (lyophilised) to obtain the acid addition salt asa solid. Alternatively, a compound of formula (I) may be dissolved in asuitable solvent, for example an alcohol such as isopropanol, and theacid may be added in the same solvent or another suitable solvent. Theresulting acid addition salt may then be precipitated directly, or byaddition of a less polar solvent such as diisopropyl ether or hexane,and isolated by filtration.

Suitable addition salts are formed from inorganic or organic acids whichform non-toxic salts and examples are hydrochloride, hydrobromide,hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, trifluoroacetate, maleate, malate, fumarate,lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate,oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl oraryl sulphonates (eg methanesulphonate, ethanesulphonate,benzenesulphonate or p-toluenesulphonate) and isethionate.Representative examples include trifluoroacetate and formate salts, forexample the bis or tris trifluoroacetate salts and the mono or diformatesalts, in particular the tris or bis trifluoroacetate salt and themonoformate salt.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compounds of the invention arewithin the scope of the invention. The salts of the compound of Formula(I) may form solvates (e.g. hydrates) and the invention also includesall such solvates.

The term “prodrug” as used herein means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects.

The compounds of the invention are proposed for use in the treatment of,inter alia, chronic inflammatory disorders. By treating or treatment ismeant at least one of:

(i). preventing or delaying the appearance of clinical symptoms of thedisease developing in a mammal;(ii). inhibiting the disease i.e. arresting, reducing or delaying thedevelopment of the disease or a relapse thereof or at least one clinicalor subclinical symptom thereof, or(iii). relieving or attenuating one or more of the clinical orsubclinical symptoms of the disease.

The benefit to a subject to be treated is either statisticallysignificant or at least perceptible to the patient or to the physician.In general a skilled man can appreciate when “treatment” occurs.

The word “treatment” is also used herein to cover prophylactictreatment, i.e. treating subjects who are at risk of developing adisease in question.

The compounds of the invention can be used on any animal subject, inparticular a mammal and more particularly to a human or an animalserving as a model for a disease (e.g. mouse, monkey, etc.).

An “effective amount” means the amount of a compound that, whenadministered to an animal for treating a state, disorder or condition,is sufficient to effect such treatment. The “effective amount” will varydepending on the compound, the disease and its severity and the age,weight, physical condition and responsiveness of the subject to betreated and will be ultimately at the discretion of the attendantdoctor.

While it is possible that, for use in the methods of the invention, acompound of formula I may be administered as the bulk substance, it ispreferable to present the active ingredient in a pharmaceuticalformulation, for example, wherein the agent is in admixture with apharmaceutically acceptable carrier selected with regard to the intendedroute of administration and standard pharmaceutical practice.

The term “carrier” refers to a diluent, excipient, and/or vehicle withwhich an active compound is administered. The pharmaceuticalcompositions of the invention may contain combinations of more than onecarrier. Such pharmaceutical carriers can be sterile liquids, such aswater, saline solutions, aqueous dextrose solutions, aqueous glycerolsolutions, and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. Water or aqueous solution saline solutions and aqueousdextrose and glycerol solutions are preferably employed as carriers,particularly for injectable solutions. Suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E. W. Martin,18th Edition. The choice of pharmaceutical carrier can be selected withregard to the intended route of administration and standardpharmaceutical practice. The pharmaceutical compositions may compriseas, in addition to, the carrier any suitable binder(s), lubricant(s),suspending agent(s), coating agent(s), and/or solubilizing agent(s).

It will be appreciated that pharmaceutical compositions for use inaccordance with the present invention may be in the form of oral,parenteral, transdermal, inhalation, sublingual, topical, implant,nasal, or enterally administered (or other mucosally administered)suspensions, capsules or tablets, which may be formulated inconventional manner using one or more pharmaceutically acceptablecarriers or excipients.

There may be different composition/formulation requirements depending onthe different delivery systems. Likewise, if the composition comprisesmore than one active component, then those components may beadministered by the same or different routes.

The pharmaceutical formulations of the present invention can be liquidsthat are suitable for oral, mucosal and/or parenteral administration,for example, drops, syrups, solutions, injectable solutions that areready for use or are prepared by the dilution of a freeze-dried productbut are preferably solid or semisolid as tablets, capsules, granules,powders, pellets, pessaries, suppositories, creams, salves, gels,ointments; or solutions, suspensions, emulsions, or other forms suitablefor administration by the transdermal route or by inhalation.

The compounds of the invention can be administered for immediate-,delayed-, modified-, sustained-, pulsed-or controlled-releaseapplications.

In one aspect, oral compositions are slow, delayed or positioned release(e.g., enteric especially colonic release) tablets or capsules. Thisrelease profile can be achieved without limitation by use of a coatingresistant to conditions within the stomach but releasing the contents inthe colon or other portion of the GI tract wherein a lesion orinflammation site has been identified or a delayed release can beachieved by a coating that is simply slow to disintegrate or the two(delayed and positioned release) profiles can be combined in a singleformulation by choice of one or more appropriate coatings and otherexcipients. Such formulations constitute a further feature of thepresent invention.

Pharmaceutical compositions can be prepared by mixing a therapeuticallyeffective amount of the active substance with a pharmaceuticallyacceptable carrier that can have different forms, depending on the wayof administration. Typically composition components include one or moreof binders, fillers, lubricants, odorants, dyes, sweeteners,surfactants, preservatives, stabilizers and antioxidants.

The pharmaceutical compositions of the invention may contain from 0.01to 99% weight-per volume of the active material. The therapeutic doseswill generally be between about 10 and 2000 mg/day and preferablybetween about 30 and 1500 mg/day. Other ranges may be used, including,for example, 50-500 mg/day, 50-300 mg/day, 100-200 mg/day.

Administration may be once a day, twice a day, or more often, and may bedecreased during a maintenance phase of the disease or disorder, e.g.once every second or third day instead of every day or twice a day. Thedose and the administration frequency will depend on the clinical signs,which confirm maintenance of the remission phase, with the reduction orabsence of at least one or more preferably more than one clinical signsof the acute phase known to the person skilled in the art.

It is within the scope of the invention for a compound as describedherein to be administered in combination with another pharmaceutical,e.g. another drug with known efficacy against the disease in question.The compounds of the invention may therefore be used in combinationtherapy.

The invention will now be further described with reference to thefollowing non limiting examples:

The chemistry described in the following schemes is used to manufacturethe compounds described in the tables which follow. The startingmaterials in each scheme are readily available compounds. In general,molar equivalents of each reactant are employed.

The chemistry described in the following schemes is used to manufacturethe compounds described in the tables which follow. The startingmaterials in each scheme are readily available compounds. In general,molar equivalents of each reactant are employed.

Experimental Procedures for the Formation of Compounds

-   -   A. To a solution of thiazole (1.1 mmol) in dry THF (2 mL) under        argon atmosphere and at −78° C., n-BuLi solution (1.1 mmol, 2.5        M in hexanes) was added dropwise over a period of 5 min. After        stirring at −78° C. for 30 min, a solution of the appropriate        aldehyde (1 mmol) in dry THF (2 mL) was added and the mixture        was stirred for additional 4 hours at −78° C. Then, H₂O was        added and the mixture was extracted thrice with EtOAc. The        organic layer was dried (Na₂SO₄) and concentrated under reduced        pressure. Purification by flash eluting with the appropriate        mixture of EtOAc: petroleum ether (40-60° C.) afforded the        desired product.    -   B. To a solution of the hydroxy-heterocycle (1 mmol) in dry        CH₂Cl₂ (10 mL), Dess-Martin periodinane was added (1.5 mmol) and        the mixture was stirred for 1 h at rt. The organic solution was        washed with 10% aqueous NaHCO₃, dried over Na₂SO₄ and        concentrated under reduced pressure. The residue was purified by        column-chromatography using the appropriate mixture of EtOAc:        petroleum ether (40-60° C.) as eluent.    -   C. To a stirred solution of the carboxylic acid (1 mmol) in        CH₂Cl₂ (7 mL), 4-dimethylaminopyridine (DMAP) (1 mmol),        N,O-dimethyl hydroxyamine hydrochloride (1 mmol),        N-methylmorpholine (1 mmol) and        N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride        (WSCI.HCl) (1 mmol) were added consecutively at room        temperature. The reaction mixture was left stirring for 18 h. It        was then washed with an aqueous solution of 10% citric acid        (3×10 mL), brine (10 mL), an aqueous solution of NaHCO₃ 5% (3×10        mL) and brine (10 mL). The organic layer was dried (Na₂SO₄) and        concentrated under reduced pressure. The amide was purified by        flash chromatography eluting with the appropriate mixture of        EtOAc: petroleum ether (40-60° C.) to afford the desired        product.    -   D. To a stirred solution of acid (1 mmol) in dry CH₂Cl₂ (7 mL),        DMF (0.5 eq.) was added followed by oxalyl chloride (3 mmol) at        room temperature. The reaction mixture was left stirring for        3 h. The solvent was removed and dry Et₂O (7 mL) was added and        cooled at 0° C. Pyridine (5 mmol) was added drop-wise, followed        by drop-wise adittion of morpholine (5 mmol). The reaction        mixture was left stirring for 18 h at room temperature. Then,        H₂O (8 mL) was added and it was left stirring for 30 min. The        layers were separated and the organic layer was washed with an        aqueous solution of HCl 1N (3×10 mL), brine (1×10 mL), an        aqueous solution of NaHCO₃ 5% (3×10 mL) and brine (1×10 mL). The        organic layer was dried (Na₂SO₄) and concentrated under reduced        pressure. Purification by flash chromatography eluting with the        appropriate mixture of EtOAc: petroleum ether (40-60° C.)        afforded the desired product.    -   E. To a stirred solution of thiazole or benzothiazole (3 mmol)        in dry Et₂O (20 mL) at −78° C. under a dry argon atmosphere was        added a solution of n-BuLi (1.6 M in hexanes, 3 mmol) drop-wise        over a period of 10 min. The resulting orange solution was        stirred for 45 min. Then, a solution of the amide (1 mmol) in        dry Et₂O (2 mL) was slowly added giving the mixture a dark brown        color. After stirring for 30 min. at −78° C., the mixture was        allowed to warm up to room temperature over a period of 2 h.        Then, saturated aqueous ammonium chloride solution was added and        the mixture was extracted with ether (2×10 mL). The combined        extracts were washed with brine and then dried over Na₂SO₄ and        concentrated under reduced pressure. Purification by flash        chromatography eluting with the appropriate mixture of EtOAc:        petroleum ether (40-60° C.) afforded the desired product.    -   F. To a stirred solution of the ester (1 mmol) in dry Et₂O (10        mL) was added dropwise DIBALH (1.1 mL, 1.0 M in hexane, 1.1        mmol) at 0° C. The reaction was stirred for 10 min and then        quenched with H₂O. The mixture was stirred for 30 min, dried        over Na₂SO₄, and filtered through a pad of Celite. The solvent        was evaporated and the crude product was purified by silica gel        column chromatography.    -   G. To a solution of the alcohol (1 mmol) in a mixture of        toluene-EtOAc (6 mL), a solution of NaBr (1.05 mmol) in water        (0.5 mL) was added, followed by AcNH-TEMPO (0.01 mmol). To the        resulting biphasic system, which was cooled at −5° C., an        aqueous solution of 0.35 M NaOCl (3.14 mL, 1.10 mmol) containing        NaHCO₃ (3 mmol) was added dropwise while stirring vigorously at        −5° C. over a period of 1 h. After the mixture had been stirred        for a further 15 min at 0° C., EtOAc (6 mL) and H₂O (2 mL) were        added. The aqueous layer was separated and washed with EtOAc (4        mL). The combined organic layers were washed consecutively with        5% aqueous citric acid (6 mL) containing 5% KI, 10% aqueous        Na₂S₂O₃ (6 mL), and brine and dried over Na₂SO₄. The solvents        were evaporated under reduced pressure, and the residue was used        immediately in the next step without any purification.    -   H. A solution of the aldehyde (1 mmol) in CH₂Cl₂ (2 mL) was        added to a mixture of tert-butyl dimethylsilylcyanide (1 mmol),        potassium cyanide (0.17 mmol) and 18-crown-6 (0.4 mmol) under        argon atmosphere. The mixture was stirred for 1 h. The solvent        was evaporated and the crude product was purified by silica gel        column chromatography eluting with the appropriate mixture of        EtOAc: petroleum ether (40-60° C.) to afford the desired        product.    -   I. To a solution of the cyanide (1 mmol) in CH₂Cl₂ (20 mL) at        0° C. was added 30% H₂O₂ (0.5 mL), tetrabutyammonium hydrogen        sulfate (0.2 mmol) and an aqueous solution of 0.5 N NaOH (1.2        mmol). The reaction mixture was stirred in a sealed flask for 18        h during which additional H₂O₂ (0.5 mL) were added thrice. H₂O        and CH₂Cl₂ were added and the organic layer was separated,        washed with brine and dried over Na₂SO₄. The crude product was        purified by silica gel column chromatography eluting with the        appropriate mixture of EtOAc: petroleum ether (40-60° C.) to        afford the desired product.    -   J. Lawesson's reagent (0.6 mmol) was added to a solution of the        amide (1 mmol) in dry toluene (10 mL) under argon atmosphere.        The reaction mixture was stirred for 18 h at room temperature.        The solvent was evaporated and the crude product was purified by        silica gel column chromatography eluting with the appropriate        mixture of EtOAc: petroleum ether (40-60° C.) to afford the        desired product.    -   K. To a solution of the thioamide (1 mmol) in ethanol (3.2 mL)        under argon atmosphere, was added ethyl bromopyruvate or ethyl        4-chloroacetoacetate (1 mmol) and concentrated H₂SO₄ (10 μL).        The reaction mixture was stirred for 18 h. The solvent was        evaporated and the crude product was purified by silica gel        column chromatography eluting with the appropriate mixture of        EtOAc: petroleum ether (40-60° C.) to afford the desired        product.    -   L. To a solution of the hydroxyl heterocyclic ester (1 mmol) in        EtOH (25 mL), an aqueous solution of 1 N NaOH (20 mmol, 20 mL)        was added. After stirring for 1 h, the solution was acidified        with aqueous solution of 1N HCl and the product was extracted        with Et₂O. The organic layer was separated, washed with brine        and dried over Na₂SO₄. The product was used in the next step        without any purification.    -   M. To a solution of the oxo heterocyclic ester (1 mmol) in EtOH        (25 mL), an aqueous solution of 20% Cs₂CO₃ (20 mmol, 20 mL) was        added. After stirring for 18 h, the solution was acidified with        aqueous solution of 1N HCl and the product was extracted with        Et₂O. The organic layer was separated, washed with brine and        dried over Na₂SO₄. The product was purified by        recrystallization.    -   N. To a stirred solution of LiAlH₄ (1M in THF, 2.9 mmol) in dry        Et₂O (5.5 mL) under argon atmosphere and at −20° C. a solution        of the ester (1 mmol) in dry Et₂O (5.5 mL) was added. The        reaction was stirred for 20 min at −20° C. and for 20 min at rt.        Then, it was cooled at 0° C. and quenched with H₂O. The mixture        was stirred for 30 min at rt. Then, additional H₂O was added and        the mixture was acidified with 1 N HCl to pH 5. The aqueous        layer was washed twice with Et₂O, and then the combined organic        layers were washed with brine, dried over Na₂SO₄, and the        solvent was evaporated. The crude product was purified by silica        gel column chromatography eluting with the appropriate mixture        of EtOAc: petroleum ether (40-60° C.) to afford the desired        product.    -   O. To a stirred solution of the alcohol (1 mmol) in acetone (4.2        mL), K₂CO₃ (3 mmol) was added followed by a catalytic amount of        KI and the appropriate bromide (1.1 mmol). The solution was        refluxed for 18 h, the solvent was evaporated, and H₂O and EtOAc        were added. The aqueous layer was washed twice with EtOAc and        then the combined organic layers were washed with brine, dried        over Na₂SO₄, and the solvent was evaporated. The crude product        was purified by silica gel column chromatography eluting with        the appropriate mixture of EtOAc: petroleum ether (40-60° C.) to        afford the desired product.    -   P. A solution of the hydroxy compound (1 mmol) in dry CH₂Cl₂ (50        mL) was treated dropwise with a solution of DAST (3 mmol) in dry        CH₂Cl₂ (2 mL) under argon atmosphere and at −78° C. The reaction        mixture was stirred for 2 h at −78° C. and for additional 16 h        at rt. Then, a saturated solution of NaHCO₃ was added until the        bubbling of CO₂ stopped. The solution was stirred for 20 min and        then H₂O and CH₂Cl₂ were added. The organic layer was separated,        dried over Na₂SO₄, filtered and evaporated, and the crude        product was purified by column chromatography on silica gel        eluting with EtOAc-petroleum ether (bp 40-60° C.) to yield the        desired fluoro derivative.    -   Q. A solution of oxalyl chloride (4 mmol) in dry CH₂Cl₂ (3 mL)        under argon atmosphere and at −60° C. was treated dropwise with        a solution of dry DMSO (8 mmol) in dry CH₂Cl₂ (3.5 mL). After 5        min, a solution of the fluoro alcohol (1 mmol) in dry CH₂Cl₂ (20        mL) was added dropwise and after additional 15 min, dry Et₃N (16        mmol) was added. The reaction mixture was stirred for 1 h to        reach room temperature. Then, the reaction mixture was poured in        ice and the aqueous layer was extracted thrice with CH₂Cl₂. The        combined organic layers were washed with brine, dried over        Na₂SO₄, and the solvent was evaporated. The crude product was        purified by silica gel column chromatography eluting with the        appropriate mixture of EtOAc: petroleum ether (40-60° C.) to        afford the desired product.    -   R. A solution of the aldehyde (1 mmol) and methyl        (triphenylphosphanylidene)acetate (1.1 mmol) in dry CH₂Cl₂ (3        mL) under argon atmosphere was refluxed for 1 h and then left        stirring for 16 h at rt. Saturated solution of NH₄Cl was added        and the aqueous layer was extracted thrice with CH₂Cl₂. The        combined organic layers were washed with brine, dried over        Na₂SO₄, and the solvent was evaporated. The crude product was        purified by silica gel column chromatography eluting with the        appropriate mixture of EtOAc: petroleum ether (40-60° C.) to        afford the desired product.    -   S. A mixture of the unsaturated ester (1 mmol) in dry        1,4-dioxane (10 mL) and a catalytic amount of 10% palladium on        activated carbon was hydrogenated for 18 h. After filtration        through a pad of celite and the solvent was removed in vacuo.        The crude product was purified by silica gel column        chromatography eluting with the appropriate mixture of EtOAc:        petroleum ether (40-60° C.) to afford the desired product.    -   T. A solution of the aldehyde (1 mmol) and NaHSO₃ (1.5 mmol in        1.3 mL H₂O) in CH₂Cl₂ (1.2 mL) was stirred for 30 min at room        temperature. After the formation of a white salt, the organic        solvent was evaporated and water (1 mL) was added. The mixture        was cooled to 0° C. and an aqueous solution of KCN (1.5 mmol in        1.3 mL H₂O) was added dropwise. The reaction mixture was stirred        for another 18 h at room temperature and then CH₂Cl₂ and water        were added. The organic layer was washed with brine and dried        (Na₂SO₄). The solvent was evaporated under reduced pressure and        the residual oil was purified by column chromatography on silica        gel eluting with the appropriate mixture of EtOAc: petroleum        ether (40-60° C.).    -   U. The cyanhydrine (1 mmol) was treated with 6N HCl (10 mL) in        MeOH for 18 h at room temperature. The organic solvent was        evaporated and a saturated aqueous solution of K₂CO₃ was added        to pH neutralization. After extraction with CH₂Cl₂ (3×15 mL),        the combined organic phases were washed with brine and dried        (Na₂SO₄). The solvent was evaporated under reduced pressure and        the residual oil was purified by column chromatography on silica        gel eluting with the appropriate mixture of EtOAc: petroleum        ether (40-60° C.).    -   V. To a stirred solution of the Z-protected amino compound (1        mmol) in MeOH (8 mL) were added successively a catalytic amount        of 10% Pd/C and anhydrous ammonium formate (5 mmol). After        stirring for 2 h at rt, the reaction mixture was filtered over        celite. The organic layer was then concentrated under reduced        pressure to yield the crude product, which was used without any        further purification.    -   W. To a stirred solution of phenylacetic acid (1.0 mmol) and the        amino component (1.0 mmol) in dry CH₂Cl₂ (10 mL), Et₃N (1.1        mmol) and subsequently 1-(3-dimethylaminopropyl)-3-ethyl        carbodiimide (WSCI) (1.1 mmol) and 1-hydroxybenzotriazole (HOBt)        (1.0 mmol) were added at 0° C. The reaction mixture was stirred        for 1 h at 0° C. and overnight at rt. The solvent was evaporated        under reduced pressure and EtOAc (20 mL) was added. The organic        layer was washed consecutively with brine, 1N HCl, brine, 5%        NaHCO₃, and brine, dried over Na₂SO₄ and evaporated under        reduced pressure. The residue was purified by column        chromatography on silica gel eluting with the appropriate        mixture of EtOAc: petroleum ether (40-60° C.).    -   X. A solution of the tert-butyl ester derivative (1 mmol) in 50%        TFA/CH₂Cl₂ (10 mL) was stirred for 1 h at room temperature. The        organic solvent was evaporated under reduced pressure to afford        the desired product.

Compounds 1-3

Characterising Data 1-(Thiazol-2-yl)hexadecan-1-ol (2a) Procedure A

White solid. Yield 51%.

m.p. 69-71° C.

¹H NMR: δ 7.68 (d, 1H, J=2.8 Hz, ArH), 7.25 (d, 1H, J=2.8 Hz, ArH), 4.97(m, 1H, CHOH), 3.14 (br s, 1H, OH), 1.86 (m, 2H, CH₂CHOH), 1.48-1.13 (m,26H, 13×CH₂), 0.86 (t, 3H, J=6.2 Hz, CH₃).

¹³C NMR: δ 175.6, 142.0, 118.8, 71.8, 38.3, 31.9, 29.7, 29.6, 29.6,29.5, 29.4, 29.3, 25.2, 22.7, 14.1.

5-Phenyl-1-(thiazol-2-yl)pentan-1-ol (2b) Procedure A

Colorless Oil. Yield 42%.

¹H NMR: δ 7.65 (d, 1H, J=3.4 Hz, ArH), 7.33-7.16 (m, 6H, Ph, ArH), 4.97(m, 1H, CHOH), 4.5 (br, 1H, OH), 2.62 (t, 2H, J=7.0 Hz, CH₂Ph),2.05-1.80 (m, 2H, CH₂CHOH), 1.74-1.45 (m, 4H, 2×CH₂).

¹³C NMR: δ 176.3, 142.3, 141.8, 128.3, 128.2, 125.6, 118.7, 71.4, 37.9,35.7, 31.1, 24.9.

(Z)-1-(Thiazol-2-yl)octadec-9-en-1-ol (2c) Procedure A

C₂₁H₃₇NOS

White oil.

¹H NMR (CDCl₃) δ: 7.69 (d, 1H, J=3.4 Hz, CHN), 7.28 (d, 1H, J=3.4 Hz,CHS), 5.34 (m, 2H, CH═CH), 4.97 (dd, 1H, J₁=7.4 Hz, J₂=5.2 Hz, CHOH),3.47 (b, 1H, OH), 2.00 (m, 6H, 3×CH₂), 1.60-1.10 (m, 22H, 11×CH₂), 0.88(t, 3H, J=6.2 Hz, CH₃).

¹³C NMR (CDCl₃) δ: 175.7, 142.0, 129.9, 129.8, 118.7, 71.8, 38.3, 31.9,29.7, 29.5, 29.3, 29.2, 27.1, 25.2, 22.6, 14.1.

(5Z,8Z,11Z,14Z)-1-(Thiazol-2-yl)icosa-5,8,11,14-tetraen-1-ol (2d)Procedure A

C₂₃H₃₅NOS

MW: 373.60.

White oil.

¹H NMR (CDCl₃) δ: 7.64 (d, 1H, J=3.0 Hz, ArH), 7.23 (d, 1H, J=3.0 Hz,ArH), 5.56-5.21 (m, 8H, 4×CH═CH), 4.96 (dd, 1H, J₁=6.8 Hz, J₂=5.0 Hz,CHOH), 4.20-3.90 (br, 1H, OH), 2.98-2.63 (m, 6H, 3×CHCH₂CH), 2.18-1.79(m, 6H, 3×CH₂), 1.69-1.18 (m, 8H, 4×CH₂), 0.90 (t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (CDCl₃) δ: 175.8, 141.9, 130.4, 129.5, 128.5, 128.2, 128.0,127.9, 127.8, 127.5, 118.7, 71.5, 37.7, 31.4, 29.2, 27.1, 26.8, 25.5,25.4, 25.1, 22.5, 14.0.

MS (ESI) m/z (%): 373 [M⁺, 100].

1-(Thiazol-2-yl)hexadecan-1-one (3a)

Procedure B

C₁₉H₃₃NOS

MW: 323.54.

White solid.

m.p.: 39-41° C.

¹H NMR (200 MHz, CDCl₃) δ=7.98 (d, 1H, J=3.0 Hz, ArH), 7.65 (d, 1H,J=3.0 Hz, ArH), 3.14 (t, 2H, J=7.4 Hz, CH₂CO), 1.81-1.68 (m, 2H,CH₂CH₂CO), 1.42-1.10 (m, 24H, 12×CH₂), 0.86 (t, 3H, J=5.0 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=194.1, 167.3, 144.6, 126.0, 38.5, 31.9, 29.6,29.4, 29.3, 29.2, 24.0, 22.7, 14.1.

MS (ESI) m/z (%): 324 [M+H, 100]⁺.

5-Phenyl-1-(thiazol-2-yl)pentan-1-one (3b) Procedure B

C₁₄H₁₅NOS

MW: 245.34.

Yellow oil.

¹H NMR (200 MHz, CDCl₃) δ=8.00 (d, 1H, J=3.0 Hz, ArH), 7.66 (d, 1H,J=2.8 Hz, ArH), 7.33-7.13 (m, 5H, Ph), 3.21 (t, 2H, J=6.6 Hz, CH₂CO),2.68 (t, 2H, J=7.6 Hz, PhCH₂), 1.92-1.65 (m, 4H, 2×CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=193.8, 167.1, 144.5, 142.0, 128.3, 128.2,126.1, 125.6, 38.2, 35.6, 30.9, 23.6.

(Z)-1-(Thiazol-2-yl)octadec-9-en-1-one (3c) Procedure B

C₂₁H₃₅NOS

Yellowish oil.

¹H NMR (CDCl₃) δ: 8.00 (d, 1H, J=3.0 Hz, CHN), 7.66 (d, 1H, J=3.0 Hz,CHS), 5.34 (m, 2H, CH═CH), 3.16 (t, 2H, J=8.0 Hz, CH₂CO), 2.01 (m, 4H,2×CH₂CH═), 1.80-1.60 (m, 2H, CH₂), 1.60-1.10 (m, 20H, 10×CH₂), 0.88 (t,3H, J=6.2 Hz, CH₃). ¹³C NMR (CDCl₃) δ: 194.1, 167.4, 144.6, 130.0,129.7, 126.0, 38.5, 32.6, 31.9, 29.7, 29.5, 29.3, 29.2, 29.1, 27.2,24.0, 22.7, 14.1.

(5Z,8Z,11Z,14Z)-1-(Thiazol-2-yl)icosa-5,8,11,14-tetraen-1-one (3d)Procedure B

C₂₃H₃₃NOS

Yellowish oil.

¹H NMR (CDCl₃) δ: 8.00 (d, 1H, J=2.8 Hz, ArH), 7.66 (d, 1H, J=2.8 Hz,ArH), 5.42-5.21 (m, 8H, 4×CH═CH), 3.19 (t, 2H, J=7.2 Hz, CH₂CO),2.88-2.63 (m, 6H, 3×CHCH₂CH), 2.25-2.20 (m, 4H, 2×CH₂), 1.45-1.17 (m,2H, CH₂), 1.40-1.20 (m, 6H, 3×CH₂), 0.88 (t, 3H, J=6.4 Hz, CH₃).

¹³C NMR (CDCl₃) δ: 193.9, 167.2, 144.6, 130.4, 129.1, 128.9, 128.5,128.2, 128.1, 127.9, 127.5, 126.1, 37.8, 31.5, 29.3, 29.2, 27.2, 26.6,25.6, 23.9, 22.5, 14.0.

Compounds 3 to 5 (Alternative Strategies)

N-Methoxy-N-methyl-palmitamide (4a) Procedure C

C₁₈H₃₇NO₂

MW: 299.49.

colorless oil. Yield 81%.

¹H NMR (200 MHz, CDCl₃) δ=3.66 (s, 3H, OMe), 3.16 (s, 3H, NMe), 2.39 (t,2H, J=7.6 Hz, CH₂CO), 1.70-1.57 (m, 2H, CH₂CH₂CO), 1.23-1.08 (m, 24H,12×CH₂), 0.86 (t, 3H, J=3.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=174.6, 61.0, 31.8, 29.5, 29.4, 29.3, 24.8,24.5, 22.5, 13.9. MS (ESI) m/z (%): 300 [M+H, 100]⁺.

N-Methoxy-N-methyl-5-phenylpentanamide (4b) (by the Weinreb method)Procedure C

C₁₃H₁₉NO₂

MW: 221.30.

Colorless oil. Yield 81%.

¹H NMR (200 MHz, CDCl₃) δ=7.33-7.12 (m, 5H, Ph), 3.65 (s, 3H, OMe), 3.17(s, 3H, NMe), 2.65 (t, 2H, J=7.2 Hz, PhCH₂), 2.44 (t, 2H, J=7.2 Hz,CH₂CO), 1.72-1.66 (m, 4H, 2×CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=174.6, 142.2, 128.2, 128.1, 125.6, 61.0, 35.6,31.6, 31.1, 24.2.

MS (ESI) m/z (%): 222 [M+H, 100]⁺.

General Procedure for the Synthesis of Morpholine Amides

To a stirred solution of acid (1 eq.) in dry CH₂Cl₂ (7 mL), DMF (0.5eq.) was added followed by oxalyl chloride (3 eq.) at room temperature.The reaction mixture was left stirring for 3 h. The solvent was removedand dry Et₂O (7 mL) was added and cooled at 0° C. Pyridine (5 eq.) wasadded drop-wise, followed by drop-wise adittion of morpholine (5 eq.).The reaction mixture was left stirring for 18 h at room temperature.Then, H₂O (8 mL) was added and it was left stirring for 30 min. Thelayers were separated and the organic layer was washed with an aqueoussolution of HCl 1N (3×10 mL), brine (1×10 mL), an aqueous solution ofNaHCO₃ 5% (3×10 mL) and brine (1×10 mL). The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure. Purification by flashchromatography eluting with the appropriate mixture of EtOAc: pet. ether(40-60° C.) afforded the desired product.

1-Morpholinohexadecan-1-one (5a) Procedure D

C₂₀H₃₉NO₂

MW: 325.53.

White solid. Yield 99%.

m.p.: 45-46° C.

¹H NMR (200 MHz, CDCl₃) δ=3.66-3.60 (m, 6H, CH₂OCH₂, CHHNCHH), 3.43-3.38(m, 2H, CHHNCHH), 2.28 (t, 2H, J=7.2 Hz, CH₂CO), 1.63-1.52 (m, 2H,CH₂CH₂CO), 1.34-1.06 (m, 24H, 12×CH₂), 0.85 (t, 3H, J=5.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=171.8, 66.8, 66.6, 45.9, 41.7, 33.0, 31.8,29.6, 29.5, 29.4, 29.3, 29.2, 25.2, 22.6, 14.0.

MS (ESI) m/z (%): 326 [M+H, 100]⁺.

1-Morpholino-5-phenylpentan-1-one (5b) Procedure D

C₁₅H₂₁NO₂

MW: 247.33.

Colorless oil. Yield 74% (1.025 g).

¹H NMR (200 MHz, CDCl₃) δ=7.26-7.09 (m, 5H, Ph), 3.64-3.42 (m, 6H,CH₂OCH₂, CHHNCHH), 3.41-3.23 (m, 2H, CHHNCHH), 2.61 (t, 2H, J=7.0 Hz,PhCH₂), 2.27 (t, 2H, J=7.2 Hz, CH₂CO), 1.69-1.60 (m, 4H, 2×CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=171.3, 141.9, 128.2, 128.1, 125.5, 66.7, 66.4,45.7, 41.6, 35.5, 32.7, 30.9, 24.6.

MS (ESI) m/z (%): 248 [M+H, 100]⁺, 270 [M+23, 23].

Synthesis of 2-oxo-thiazoles Using the Weinreb and Morpholino AmideMethod

To a stirred solution of thiazole (3 eq.) in dry Et₂O (20 mL) at −78° C.under a dry argon atmosphere was added a solution of n-BuLi (1.6 M inhexanes, 3 eq.) drop-wise over a period of 10 min. The resulting orangesolution was stirred for 45 min. Then a solution of the amide (1 eq.) indry Et₂O (2 mL) was slowly added giving the mixture a dark brown color.After stirring for 30 min. at −78° C., the mixture was allowed to warmup to room temperature over a period of 2 h. Then, saturated aqueousammonium chloride solution was added and the mixture was extracted withether (2×10 mL). The combined extracts were washed with brine and thendried over Na₂SO₄ and concentrated under reduced pressure. Purificationby flash chromatography eluting with the appropriate mixture of EtOAc:pet. ether (40-60° C.) afforded the desired product.

1-(Thiazol-2-yl)hexadecan-1-one (3a) Procedure E

Yield when the Weinreb amide was used: 73%.

Yield when the morpholine amide was used: 98%.

5-Phenyl-1-(thiazol-2-yl)pentan-1-one (3b) Procedure E

Yield when the Weinreb amide was used: 85%.

Yield when the morpholine amide was used: 86%.

Compounds 6 to 9

3-(4-(Hexyloxy)phenyl)propanal (7) Procedure F then G

C₁₅H₂₂O₂

MW: 234.33

Orange oil. Yield 64%.

¹H NMR (200 MHz, CDCl₃) δ=9.80 (s, 1H, CHO), 7.09 (d, 2H, J=8.4 Hz, CH),6.82 (d, 2H, J=8.6 Hz, 2×CH), 3.92 (t, 2H, J=6.4 Hz, CH₂), 3.00-2.85 (m,2H, CH₂), 2.80-2.65 (m, 2H, CH₂), 1.85-1.65 (m, 2H, CH₂), 1.50-1.20 (m,6H, 3×CH₂), 0.92 (m, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=201.7, 157.6, 132.0, 129.1, 114.5, 67.9, 45.5,31.5, 29.2, 27.2, 25.7, 22.5, 14.0

3-(4-(Hexyloxy)phenyl)-1-(thiazol-2-yl)propan-1-ol (8) Procedure A

C₁₈H₂₅NO₂S

MW: 319.46

Colorless oil. Yield 66%.

¹H NMR (200 MHz, CDCl₃) δ=7.65 (d, 1H, J=3.2 Hz, ArH), 7.24 (d, 1H,J=3.4 Hz, ArH), 7.07 (d, 2H, J=8.8 Hz, 2×CH), 6.79 (d, 2H, J=8.6 Hz,2×CH), 4.96 (dd, 1H, J=7.6 Hz, J₂=5.0 Hz, CH), 3.90 (t, 2H, J=6.4 Hz,CH₂O), 2.80-2.60 (m, 2H, CH₂), 2.25-2.05 (m, 2H, CH₂), 1.85-1.65 (m, 2H,CH₂), 1.50-1.30 (m, 6H, 3×CH₂), 0.88 (t, 3H, J=6.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=175.9, 157.4, 142.0, 133.0, 129.3, 118.8,114.4, 70.9, 67.9, 39.9, 31.5, 30.5, 29.2, 25.6, 22.5, 14.0.

3-(4-(Hexyloxy)phenyl)-1-(thiazol-2-yl)propan-1-one (9) Procedure B

C₁₈H₂₃NO₂S

MW: 317.45

Yellowish oil. Yield 78%.

¹H NMR (200 MHz, CDCl₃) δ=7.95 (d, 1H, J=3.2 Hz, ArH), 7.62 (d, 1H,J=3.4 Hz, ArH), 7.15 (d, 2H, J=8.8 Hz, CH), 6.81 (d, 2H, J=8.4 Hz, CH),3.90 (t, 2H, J=6.6 Hz, CH₂O), 3.45 (t, 2H, J=7.2 Hz, CH₂), 3.01 (t, 2H,J=3.8 Hz, CH₂), 1.90-1.64 (m, 2H, CH₂), 1.58-1.20 (m, 6H, 3×CH₂), 0.89(t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=193.1, 167.1, 157.5, 144.6, 132.5, 129.3,126.1, 114.5, 68.0, 40.3, 31.5, 29.2, 28.9, 25.7, 22.6, 14.0.

MS (ESI) m/z (%): 318 [M+H, 100]⁺.

Compounds 10 to 15

2-(tert-Butyldimethylsilyloxy)heptadecanenitrile (11a) Procedure H

C₂₃H₄₇NOSi

MW: 381.71

Colorless oil. Yield 85%.

¹H NMR (200 MHz, CDCl₃) δ=4.41 (t, 1H, J=6.4 Hz, CH), 1.70-1.90 (m, 2H,CH₂), 1.40-1.55 (m, 2H, CH₂), 1.30-1.15 (m, 24H, 12×CH₂), 1.03-0.82 (m,12H, 4×CH₃), 0.19 (s, 3H, CH₃), 0.14 (s, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=120.1, 61.9, 36.3, 31.9, 29.6, 29.5, 29.4,29.3, 28.9, 25.5, 24.5, 22.7, 18.0, 14.1, −5.2, −5.4.

2-(tert-Butyldimethylsilyloxy)-6-phenylhexanenitrile (11b) Procedure H

C₁₈H₂₉NOSi

MW: 303.51

Colorless oil. Yield 82%.

¹H NMR (CDCl₃): δ=7.34-7.20 (m, 5H, Ph), 4.44 (t, 1H, J=6.6 Hz, CH),2.68 (t, 2H, J=7.4 Hz, 1.88-1.80 (m, 2H, CH₂), 1.76-1.69 (m, 2H, CH₂),1.68-1.58 (m, 2H, CH₂), 0.97 (s, 9H, 3×CH₃), 0.23 (s, 3H, CH₃), 0.18 (s,3H, CH₃).

¹³C NMR (CDCl₃) δ=142.0, 128.3, 128.0, 125.8, 120.1, 61.8, 36.1, 35.6,30.8, 25.7, 25.5, 24.1, 18.0, −5.2, −5.4.

2-(tert-Butyldimethylsilyloxy)heptadecanamide (12a) Procedure I

C₂₃H₄₉NO₂Si

MW: 399.73

Yellow oil. Yield 63%.

¹H NMR (200 MHz, CDCl₃) δ=6.49 (s, 1H, NHH), 6.14 (s, 1H, NHH), 4.10 (t,1H, J=5.0 Hz, CH), 1.80-1.56 (m, 2H, CH₂), 1.40-1.10 (m, 26H, 13×CH₂),0.95-0.80 (m, 12H, 4×CH₃), 0.17 (s, 3H, CH₃), 0.14 (s, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ 177.3, 73.4, 35.1, 31.9, 29.7, 29.6, 29.5,29.4, 29.3, 25.7, 24.1, 22.7, 18.0, 14.1, −4.9, −5.3.

MS (ESI) m/z (%) δ=400 [M+H, 40]⁺, 422 [M+Na, 100]⁺.

2-(tert-Butyldimethylsilyloxy)-6-phenylhexanamide (12b) Procedure I

C₁₈H₃₁NO₂Si

MW: 321.53

Colorless oil. Yield 100%.

¹H NMR (CDCl₃): δ=7.28-7.15 (m, 5H, Ph), 6.51 (s, 1H, NH), 5.61 (s, 1H,NH), 4.16 (t, 1H, J=6.6 Hz, CH), 2.62 (t, 2H, J=7.4 Hz, CH₂), 1.77-1.32(m, 6H, 3×CH₂), 0.91 (s, 9H, 3×CH₃), 0.06 (s, 6H, 2×CH₃).

¹³C NMR (CDCl₃): δ=177.4, 142.3, 128.2, 128.1, 125.5, 73.2, 35.6, 34.8,31.2, 25.6, 23.8, 17.8, −5.0, −5.4.

MS (ESI) m/z (%): 322 [M+H, 100]⁺.

2-(tert-Butyldimethylsilyloxy)heptadecanethioamide (13a) Procedure J

C₂₃H₄₉NOSSi

MW: 415.79

Yellowish oil. Yield 84%.

¹H NMR (200 MHz, CDCl₃) δ=7.96 (s, 1H, NHH), 7.74 (s, 1H, NHH), 4.56 (t,1H, J=5.0 Hz, CH), 1.90-1.70 (m, 2H, CH₂), 1.47-1.15 (m, 26H, 13×CH₂),1.00-0.83 (m, 12H, 4×CH₃), 0.12 (s, 3H, CH₃), 0.09 (s, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=210.3, 80.1, 38.0, 32.1, 29.9, 29.8, 29.7,29.6, 26.0, 25.7, 24.1, 22.9, 18.3, 14.3, −4.7, −4.9.

MS (ESI) m/z (%): 416 [M+H, 90]⁺.

2-(tert-Butyldimethylsilyloxy)-6-phenylhexanethioamide (13b) Procedure J

C₁₈H₃₁NOSSi

MW: 337.60

Yellowish oil. Yield 64%.

¹H NMR (CDCl₃): δ=8.28 (s, 1H, NH), 7.98 (s, 1H, NH), 7.24-7.10 (m, 5H,Ph), 4.52 (t, 1H, J=6.6 Hz, CH), 2.57 (t, 2H, J=7.4 Hz, CH₂), 1.95-1.80(m, 2H, CH₂), 1.62-1.45 (m, 2H, CH₂), 1.42-1.25 (m, 2H, CH₂), 0.88 (s,9H, 3×CH₃), 0.06 (s, 3H, SiCH₃), 0.04 (s, 3H, SiCH₃).

¹³C NMR (CDCl₃): 209.6, 142.3, 128.3, 128.1, 125.5, 79.6, 37.4, 35.6,31.2, 25.6, 23.5, 17.9, −5.1, −5.3.

MS (ESI) m/z (%): 338 [M+H, 100]⁺.

Ethyl 2-(1-hydroxyhexadecyl)thiazole-4-carboxylate (14a) Procedure K

C₂₂H₃₉NO₃S

MW: 397.61

Yellowish solid. Yield 74%.

¹H NMR (200 MHz, CDCl₃) δ=8.06 (s, 1H, CH), 5.03 (dd, 1H, J₁=4.5 Hz,J₂=8.1 Hz, CH), 4.36 (q, 2H, J=7.1 Hz, CH₂), 3.10-2.90 (br, 1H, OH),2.00-1.60 (m, 2H, CH₂), 1.35 (t, 3H, J=7.1 Hz, CH₃), 1.40-1.10 (m, 26H,13×CH₂), 0.85 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=177.3, 161.4, 146.6, 127.1, 71.8, 61.3, 38.1,31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 25.5, 25.1, 22.6, 14.2, 14.0.

Ethyl 2-(1-hydroxy-5-phenylpentyl)thiazole-4-carboxylate (14b) ProcedureK

C₁₇H₂₁NO₃S

MW: 319.42

Yellowish oil. Yield 45%.

¹H NMR (CDCl₃): δ=8.03 (s, 1H, ArH), 7.25-7.10 (m, 5H, Ph), 5.11-5.00(m, 1H, CH), 4.33 (q, 2H, J=5.8 Hz, OCH₂), 4.10-3.95 (m, 1H, OH), 2.56(t, 2H, J=7.0 Hz, CH₂), 1.85-1.78 (m, 2H, CH₂), 1.62-1.41 (m, 2H, CH₂),1.32 (t, 3H, J=5.8 Hz, CH₃), 1.24-1.20 (m, 2H, CH₂).

¹³C NMR (CDCl₃): δ=177.4, 161.3, 146.4, 142.2, 128.2, 128.1, 127.2,125.5, 71.5, 61.3, 37.8, 35.5, 30.9, 24.7, 14.2.

Ethyl 2-palmitoylthiazole-4-carboxylate (15a) Procedure B

C₂₂H₃₇NO₃S

MW: 395.60

White solid. Yield 82%.

¹H NMR (200 MHz, CDCl₃): δ=8.41 (s, 1H, CH), 4.46 (q, 2H, J=6.8 Hz,CH₂), 3.23 (t, 2H, J=7.4 Hz, CH₂), 1.85-1.60 (m, 4H, 2×CH₂), 1.43 (t,3H, J=6.8 Hz, CH₃), 1.42-1.00 (m, 22H, 11×CH₂), 0.88 (t, 3H, J=6.8 Hz,CH₃).

¹³C NMR (50 MHz, CDCl₃): δ=194.3, 167.9, 161.1, 148.9, 133.2, 62.0,38.6, 32.1, 29.9-29.8, 29.7, 29.6, 29.5, 29.3, 23.8, 22.9, 14.5, 14.3.

MS (ESI) m/z (%): 418 [M+Na, 100]⁺.

Ethyl 2-(5-phenylpentanoyl)thiazole-4-carboxylate (15b) Procedure B

C₁₇H₁₉NO₃S

MW: 317.40

Yellowish oil. Yield 81%

¹H NMR (CDCl₃): δ=8.38 (s, 1H, ArH), 7.24-7.13 (m, 5H, Ph), 4.42 (q, 2H,J=5.8 Hz, OCH₂), 3.23 (t, 2H, J=5.8 Hz, CH₂), 2.63 (t, 2H, J=7.0 Hz,CH₂CO), 1.81-1.65 (m, 4H, 2×CH₂), 1.39 (t, 3H, J=5.8 Hz, CH₃).

¹³C NMR (CDCl₃): 193.8, 167.4, 160.8, 148.6, 142.0, 133.1, 128.3, 128.2,125.7, 61.8, 38.1, 35.6, 30.7, 23.2, 14.3.

MS (ESI) m/z (%): 318 [M+H, 100]⁺.

Compounds 16 to 19

5-(4-(Hexyloxy)phenyl)pentanal (17) Procedure N then G

C₁₇H₂₆O₂

MW: 262.39.

Yellowish oil. Yield 97%.

¹H NMR (200 MHz, CDCl₃) δ=9.73 (t, 1H, J=1.8 Hz, CHO), 7.06 (d, 2H,J=8.6 Hz, CH, Ph), 6.81 (d, 2H, J=8.6 Hz, CH, Ph), 3.92 (t, 2H, J=6.4Hz, CH₂OPh), 2.56 (t, 2H, J=7.0 Hz, PhCH₂), 2.47-2.35 (m, 2H, CH₂CHO),1.81-1.67 (m, 2H, CH₂CH₂OPh), 1.65-1.57 (m, 4H, 2×CH₂), 1.55-1.09 (m,6H, 3×CH₂), 0.90 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=202.3, 157.2, 133.6, 129.0, 114.2, 67.8, 43.6,34.6, 31.5, 31.0, 29.2, 25.6, 22.5, 21.5, 20.8, 13.9.

5-(4-(Hexyloxy)phenyl)-1-(thiazol-2-yl)pentan-1-ol (18) Procedure A

C₂₀H₂₉NO₂S

MW: 347.51.

Orange oil. Yield 74%.

¹H NMR (200 MHz, CDCl₃) δ=7.62 (d, 1H, J=3.2 Hz, ArH), 7.22 (d, 1H,J=3.4 Hz, ArH), 7.03 (d, 2H, J=8.8 Hz, CH, Ph), 6.77 (d, 2H, J=8.6 Hz,CH, Ph), 4.98-4.84 (m, 1H, CHOH), 4.46 (d, 1H, J=5 Hz, CHOH), 3.89 (t,2H, J=6.4 Hz, CH₂OPh), 2.52 (t, 2H, J=7 Hz, PhCH₂), 2.48-1.19 (m, 14H,7×CH₂), 0.88 (t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=176.3, 157.0, 141.9, 134.2, 129.0, 118.5,114.1, 71.5, 67.8, 38.0, 34.7, 31.5, 31.3, 29.2, 25.6, 24.7, 22.5, 20.9,14.0.

MS (ESI) m/z (%): 348 [M+H, 100]⁺.

5-(4-(Hexyloxy)phenyl)-1-(thiazol-2-yl)pentan-1-one (19) Procedure G

C₂₀H₂₇NO₂S

MW: 345.50.

Yellowish oil. Yield 89%.

¹H NMR (200 MHz, CDCl₃) δ=7.98 (d, 1H, J=3.2 Hz, ArH), 7.65 (d, 1H,J=3.4 Hz, ArH), 7.08 (d, 2H, J=8.8 Hz, CH, Ph), 6.81 (d, 2H, J=8.4 Hz,CH, Ph), 3.91 (t, 2H, J=6.6 Hz, CH₂OPh), 3.18 (t, 2H, J=6.8 Hz, CH₂CO),2.60 (t, 2H, J=7.6 Hz, PhCH₂), 1.89-1.61 (m, 6H, 3×CH₂), 1.48-1.28 (m,6H, 3×CH₂), 0.90 (t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=193.7, 167.1, 157.2, 144.5, 133.9, 129.1,126.1, 114.2, 67.8, 38.2, 34.6, 31.5, 31.1, 29.2, 25.6, 23.5, 22.5,14.0.

MS (ESI) m/z (%): 346 [M+H, 100]⁺

Compounds 20 to 24

Ethyl 4-(4-octylphenoxy)butanoate (21) Procedure O

C₂₀H₃₂O₃

MW: 320.47.

Colorless oil. Yield 100%.

¹H NMR (200 MHz, CDCl₃) δ=7.08 (d, 2H, J=7.8 Hz, CH, Ph), 6.81 (d, 2H,J=7.6 Hz, CH, Ph), 4.15 (q, 2H, J=7.0 Hz, COOCH₂), 3.99 (t, 2H, J=5.8Hz, PhOCH₂), 2.58-2.42 (m, 4H, 2×CH₂), 2.17-2.06 (m, 2H, CH₂CH₂COO),1.57-1.45 (m, 2H, CH₂CH₂Ph), 1.27 (br, 13H, 5×CH₂, CH₃), 0.89 (t, 3H,J=5.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=173.2, 156.8, 135.0, 129.1, 114.2, 66.6, 60.3,35.0, 31.7, 30.8, 29.4, 29.2, 24.6, 22.6, 14.1, 14.0.

MS (ESI) m/z (%): 321 [M+H, 100]⁺.

4-(4-Octylphenoxy)butanal (22) Procedure N then G

C₁₈H₂₈O₂

MW: 276.41.

Colorless oil. Yield 97%.

¹H NMR (200 MHz, CDCl₃) δ=9.84 (t, 1H, J=1.4 Hz, CHO), 7.09 (d, 2H,J=8.6 Hz, CH, Ph), 6.81 (d, 2H, J=8.8 Hz, CH, Ph), 3.99 (t, 2H, J=6.0Hz, PhOCH₂), 2.70-2.52 (m, 4H, 2×CH₂), 1.63-1.52 (m, 2H, CH₂CH₂Ph),1.31-1.24 (br, 10H, 5×CH₂), 0.90 (t, 3H, J=6.4 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=201.7, 156.6, 135.2, 129.2, 114.1, 66.6, 40.6,35.0, 31.8, 31.7, 29.4, 29.2, 22.6, 22.0, 14.0.

4-(4-Octylphenoxy)-1-(thiazol-2-yl)butan-1-ol (23) Procedure A

C₂₁H₃₁NO₂S

MW: 361.54.

Orange oil. Yield 73%.

¹H NMR (200 MHz, CDCl₃) δ=7.72 (d, 1H, J=3.2 Hz, ArH), 7.29 (d, 1H,J=3.2 Hz, ArH), 7.08 (d, 2H, J=8.8 Hz, CH, Ph), 6.81 (d, 2H, J=8.6 Hz,CH, Ph), 5.11 (dd, 1H, J₁=4.4 Hz, J₂=7.6 Hz, CHOH), 4.00 (t, 2H, J=6.0Hz, PhOCH₂), 3.92 (s, 1H, OH), 2.54 (t, 2H, J=7.2 Hz, CH₂Ph), 2.32-1.90(m, 4H, 2×CH₂), 1.67-1.48 (m, 2H, CH₂CH₂Ph), 1.30-1.23 (br, 10H, 5×CH₂),0.88 (t, 3H, J=6.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=175.4, 156.6, 142.0, 135.3, 129.2, 118.9,114.3, 71.5, 67.7, 35.1, 35.0, 31.9, 31.7, 29.5, 29.2, 25.2, 22.6, 14.1.

MS (ESI) m/z (%): 362 [M+H, 100]⁺.

4-(4-Octylphenoxy)-1-(thiazol-2-yl)butan-1-one (24) Procedure G

C₂₁H₂₉NO₂S

MW: 359.53.

Yellowish oil. Yield 85%.

¹H NMR (200 MHz, CDCl₃) δ=7.99 (d, 1H, J=3.0 Hz, ArH), 7.65 (d, 1H,J=3.0 Hz, ArH), 7.07 (d, 2H, J=8.6 Hz, CH, Ph), 6.80 (d, 2H, J=8.8 Hz,CH, Ph), 4.06 (t, 2H, J=6.2 Hz, PhOCH₂), 3.39 (t, 2H, J=7.2 Hz, CH₂C═O),2.54 (t, 2H, J=7.4 Hz, CH₂Ph), 2.26 (quintet, 2H, J=6.2 Hz, CH₂CH₂C═O),1.68-1.45 (m, 2H, CH₂CH₂Ph), 1.30-1.23 (br, 10H, 5×CH₂), 0.89 (t, 3H,J=6.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=193.2, 166.9, 156.7, 144.6, 135.0, 129.1,126.0, 114.2, 66.7, 35.1, 35.0, 31.8, 31.7, 29.4, 29.2, 23.6, 22.6,14.0.

MS (ESI) m/z (%): 360 [M+H, 100]⁺.

Compounds 25 to 29

Methyl 2-fluorohexadecanoate (26) Procedure P

C₁₇H₃₃FO₂

MW: 288.44.

White solid. Yield 78%.

m.p.: 36-38° C.

¹H NMR (200 MHz, CDCl₃) δ=4.91 (dt, 1H, J_(H-H)=6.0 Hz, J_(H-F)=48.8 Hz,CHF), 3.80 (s, 3H, COOCH₃), 2.00-1.77 (m, 2H, CH₂CHF), 1.49-1.18 (m,24H, 12×CH₂), 0.88 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=170.5 (d, J_(C-C-F)=24 Hz, COO), 89.0 (d,J_(C-C-F)=183 Hz, CF), 52.2, 32.3 (d, J_(C-C-F)=21 Hz, CH₂CHF), 31.9,29.6, 29.5, 29.4, 29.3, 29.0, 24.4, 24.3, 22.7, 14.1.

¹⁹F NMR (186 MHz, CDCl₃) δ=−192.5 (quintet, CHF).

2-Fluorohexadecanal (27) Procedure N then Q

C₁₆H₃₁FO

MW: 258.42.

White solid. Yield 86%.

m.p.: 68-71° C.

¹H NMR (200 MHz, CDCl₃) δ=9.76 (d, 1H, J=5.8 Hz, CHO), 4.74 (dt, 1H,J_(H-H)=4.8 Hz, J_(H-F)=49.0 Hz, CHF), 1.86-1.68 (m, 2H, CH₂CHF),1.47-1.10 (m, 24H, 12×CH₂), 0.88 (t, 3H, J=5.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=200.4 (d, J_(C-C-F)=36 Hz, CO), 95.0 (d,J_(C-F)=178 Hz, CF), 31.9, 30.3 (d, J_(C-C-F)=20 Hz, CH₂), 29.6, 29.5,29.3, 29.2, 24.2, 24.1, 22.7, 14.1.

¹⁹F NMR (186 MHz, CDCl₃) δ=−200.0 (m, CHF).

2-Fluoro-1-(thiazole-2-yl)hexadeca-1-ol (28) Procedure A

C₁₉H₃₄FNOS

MW: 343.54.

Yellowish solid. Yield 40%.

m.p.: 46-49° C.

¹H NMR (200 MHz, CDCl₃) δ=7.89 (d, 1/7H, J=3.2 Hz, ArH), 7.75 (d, 6/7H,J=3.4 Hz, ArH), 7.45 (d, 1/7H, J=3.2 Hz, ArH), 7.35 (d, 6/7H, J=3.2 Hz,ArH), 5.22-5.05 (dm, 1H, J=13.4 Hz, CHOH), 5.01-4.66 (dm, 1H, J=51.6 Hz,CHF), 4.15 (d, 2/3H, J=4.6 Hz, CHOH), 3.91 (d, 1/3H, J=5.6 Hz, CHOH),1.94-1.08 (m, 26H, 13×CH₂), 0.88 (t, 3H, J=6.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=170.0, 142.1, 119.7, 95.4 (d, J_(C-F)=173 Hz,CF), 73.2 (d, J_(C-C-F)=22 Hz, 1/3COH), 73.0 (d, J_(C-C-F)=24 Hz,2/3COH) 31.9, 30.6 (d, J_(C-C-F)=21 Hz, CH₂), 29.6, 29.5, 29.4, 29.3,25.0, 24.9, 22.7, 14.1.

¹⁹F NMR (186 MHz, CDCl₃) δ=−190.2 (m, CHF), −194.3 (m, CHF).

MS (ESI) m/z (%): 344 [M+H, 100]⁺.

2-Fluoro-1-(thiazole-2-yl)hexadeca-1-one (29) Procedure B

C₁₉H₃₂FNOS

MW: 341.53.

White solid. Yield 60%.

m.p.: 55-56° C.

¹H NMR (200 MHz, CDCl₃) δ=8.05 (d, 1H, J=3.0 Hz, ArH), 7.76 (d, 1H,J=3.0 Hz, ArH), 6.07 (ddd, 1H, J_(H-F)=49.8 Hz, J_(H-H)=3.8 Hz,J_(H-H)=8.2 Hz, CHF), 2.19-1.91 (m, 2H, CH₂CHF), 1.66-1.08 (m, 24H,12×CH₂), 0.87 (t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=189.4 (d, J_(C-C-F)=19 Hz, CO), 164.1, 145.3,127.1, 92.9 (d, J_(C-F)=182 Hz, CF), 32.8 (d, J_(C-C-F)=21 Hz, CH₂),32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3, 24.9, 22.9, 14.3.

¹⁹F NMR (186 MHz, CDCl₃) δ=−196.6 (m, CHF).

MS (ESI) m/z (%): 342 [M+H, 100]⁺.

Compounds 30 to

The following target compounds of the invention are synthesisedaccording to the protocols above:

2-(4-(Hexyloxy)phenyl)ethanol (31) Procedure O

C₁₄H₂₂O₂

MW: 222.32.

Colorless oil. Yield 97%.

¹H NMR (200 MHz, CDCl₃) δ=7.14 (d, 2H, J=8.6 Hz, CH, Ph), 6.85 (d, 2H,J=8.8 Hz, CH, Ph), 3.94 (t, 2H, J=6.4 Hz, CH₂OPh), 3.82 (t, 2H, J=5.2Hz, CH₂OH), 2.81 (t, 2H, J=6.4 Hz, PhCH₂), 1.81-1.71 (m, 2H, CH₂CH₂OPh),1.50-1.26 (m, 6H, 3×CH₂), 0.91 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=157.8, 130.2, 129.8, 114.6, 68.0, 63.7, 38.2,31.5, 29.2, 25.6, 22.5, 14.0.

2-(4-(Hexyloxy)phenyl)acetaldehyde (32) Procedure G

C₁₄H₂₀O₂

MW: 220.31.

Yellow oil. Yield 97%.

¹H NMR (200 MHz, CDCl₃) δ=9.72 (t, 1H, J=2.4 Hz, CHO), 7.13 (d, 2H,J=8.4 Hz, CH, Ph), 6.90 (d, 2H, J=8.6 Hz, CH, Ph), 3.96 (t, 2H, J=6.4Hz, CH₂OPh), 3.63 (d, 2H, J=2.4 Hz, PhCH₂), 1.92-1.74 (m, 2H,CH₂CH₂OPh), 1.54-1.27 (m, 6H, 3×CH₂), 0.92 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=199.4, 158.2, 130.3, 123.1, 114.7, 67.7, 49.4,31.2, 28.9, 25.4, 22.3, 13.7.

(E)-Methyl 4-(4-(hexyloxy)phenyl)but-2-enoate (33) Procedure R

C₁₇H₂₄O₃

MW: 276.37.

Yellowish oil. Yield 86%.

¹H NMR (200 MHz, CDCl₃) δ=7.16-7.05 (m, 3H, CH₂CHCH, CH, Ph), 6.84 (d,2H, J=8.0 Hz, CH, Ph), 5.79 (d, 1H, J=15.6 Hz, CHCOOMe), 3.94 (t, 2H,J=6.4 Hz, CH₂OPh), 3.72 (s, 3H, COOCH₃), 3.46 (d, 2H, J=6.4 Hz, PhCH₂),1.83-1.64 (m, 2H, CH₂CH₂OPh), 1.45-1.23 (m, 6H, 3×CH₂), 0.91 (t, 3H,J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=166.9, 157.9, 148.1, 129.6, 129.3, 121.5,114.6, 68.0, 51.4, 37.6, 31.5, 29.2, 25.7, 22.5, 14.0.

MS (ESI) m/z (%): 277 [M+H, 100]⁺.

Methyl 4-(4-(hexyloxy)phenyl)butanoate (34) Procedure S

C₁₇H₂₆O₃

MW: 278.39.

Colorless oil. Yield 91%.

¹H NMR (200 MHz, CDCl₃) δ=7.08 (d, 2H, J=8.6 Hz, CH, Ph), 6.83 (d, 2H,J=8.6 Hz, CH, Ph), 3.93 (t, 2H, J=6.6 Hz, CH₂OPh), 3.67 (s, 3H, COOCH₃),2.60 (t, 2H, J=7.2 Hz, PhCH₂), 2.33 (t, 2H, J=7.2 Hz, CH₂COOMe),2.05-1.89 (m, 2H, CH₂CH₂COOMe), 1.86-1.71 (m, 2H, CH₂CH₂OPh), 1.54-1.23(m, 6H, 3×CH₂), 0.92 (t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=173.9, 157.4, 133.0, 129.2, 114.3, 67.9, 51.3,34.1, 33.2, 31.5, 29.2, 26.6, 25.7, 22.5, 13.9.

4-(4-(Hexyloxy)phenyl)butanal (35) Procedure N then G

C₁₆H₂₄O₂

MW: 248.36.

Yellow oil. Yield 99%.

¹H NMR (200 MHz, CDCl₃) δ=9.76 (t, 1H, J=1.6 Hz, CHO), 7.08 (d, 2H,J=8.6 Hz, CH, Ph), 6.83 (d, 2H, J=8.6 Hz, CH, Ph), 3.94 (t, 2H, J=6.6Hz, CH₂OPh), 2.61 (t, 2H, J=7.4 Hz, PhCH₂), 2.49-2.37 (m, 2H, CH₂CHO),2.06-1.90 (m, 2H, CH₂CH₂CHO), 1.86-1.71 (m, 2H, CH₂CH₂OPh) 1.49-1.27 (m,6H, 3×CH₂), 0.91 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=202.4, 157.4, 133.0, 129.2, 114.4, 68.0, 43.1,34.1, 31.6, 29.3, 25.7, 23.8, 22.6, 14.0.

5-(4-(Hexyloxy)phenyl)-2-hydroxypentanenitrile (36) Procedure T

C₁₇H₂₅NO₂

MW: 275.39.

Colorless oil. Yield 74%.

¹H NMR (200 MHz, CDCl₃) δ=7.08 (d, 2H, J=8.8 Hz, CH, Ph), 6.83 (d, 2H,J=8.8 Hz, CH, Ph), 4.43 (t, 1H, J=6.2 Hz, CHOH), 3.94 (t, 2H, J=6.6 Hz,CH₂OPh), 2.63 (t, 2H, J=6.4 Hz, PhCH₂), 2.28 (br s, 1H, OH), 1.93-1.61(m, 6H, 3×CH₂), 1.53-1.23 (m, 6H, 3×CH₂), 0.91 (t, 3H, J=6.8 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=157.4, 132.9, 129.2, 119.9, 114.5, 68.0, 61.0,34.5, 34.0, 31.5, 29.2, 26.3, 25.7, 22.5, 14.0.

MS (ESI) m/z (%): 293 [M+H₂O, 100]⁺.

Methyl 5-(4-(hexyloxy)phenyl)-2-hydroxypentanoate (37) Procedure U

C₁₈H₂₈O₄

MW: 308.41.

Colorless oil. Yield 86%.

¹H NMR (200 MHz, CDCl₃) δ=7.08 (d, 2H, J=8.6 Hz, CH, Ph), 6.81 (d, 2H,J=8.6 Hz, CH, Ph), 4.20 (t, 1H, J=6.8 Hz, CHOH), 3.93 (t, 2H, J=6.6 Hz,CH₂OPh), 3.78 (s, 3H, COOCH₃), 3.00 (br s, 1H, CHOH), 2.58 (t, 2H, J=6.6Hz, PhCH₂), 1.86-1.55 (m, 6H, 3×CH₂), 1.52-1.17 (m, 6H, 3×CH₂), 0.91 (t,3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=175.5, 157.2, 133.7, 129.1, 114.3, 70.3, 67.9,52.4, 34.5, 33.8, 31.5, 29.2, 26.7, 25.7, 22.5, 14.0.

MS (ESI) m/z (%): 309 [M+H, 100]⁺.

Methyl 2-fluoro-5-(4-(hexyloxy)phenyl)pentanoate (38) Procedure P

C₁₈H₂₇FO₃

MW: 310.40.

Colorless oil. Yield 37% (182 mg).

¹H NMR (200 MHz, CDCl₃) δ=7.08 (d, 2H, J=8.6 Hz, CH, Ph), 6.83 (d, 2H,J=8.8 Hz, CH, Ph), 4.93 (dt, 1H, J_(H-H)=5.8 Hz, J_(H-F)=50.2 Hz, CHF),3.94 (t, 2H, J=6.6 Hz, CH₂OPh), 3.79 (s, 3H, COOCH₃), 2.61 (t, 2H, J=7.4Hz, PhCH₂), 2.05-1.62 (m, 6H, 3×CH₂), 1.56-1.23 (m, 6H, 3×CH₂), 0.91 (t,3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=170.3 (d, J_(C-C-F)=23 Hz, COO), 157.4, 133.2,129.2, 114.4, 88.8 (d, J_(C-F)=183 Hz, CF), 68.0, 52.3, 34.3, 32.0,31.6, 29.3, 26.3, 25.7, 22.6, 14.0.

¹⁹F NMR (186 MHz, CDCl₃) δ=−192.4 (m, CHF).

MS (ESI) m/z (%): 328 [M+H₂O, 100]⁺, 311 [M+H, 15]⁺.

2-Fluoro-5-(4-(hexyloxy)phenyl)pentanal (39) Procedure N then Q

C₁₇H₂₅FO₂

MW: 280.38.

Yellow oil. Yield 50%.

¹H NMR (200 MHz, CDCl₃) δ=9.74 (d, 1H, J=6.2 Hz, CHO), 7.08 (d, 2H,J=8.4 Hz, CH, Ph), 6.84 (d, 2H, J=8.4 Hz, CH, Ph), 4.76 (dm, 1H,J_(H-F)=51.4 Hz, CHF), 3.94 (t, 2H, J=6.6 Hz, CH₂OPh), 2.62 (t, 2H,J=7.2 Hz, PhCH₂), 1.93-1.72 (m, 6H, 3×CH₂), 1.54-1.24 (m, 6H, 3×CH₂),0.93 (t, 3H, J=6.6 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=200.0 (d, J_(C-C-F)=34 Hz, CHO), 157.4, 133.0,129.2, 114.4, 94.8 (d, J_(C-F)=178 Hz, CF), 67.9, 34.3, 31.5, 29.6 (d,J_(C-C-F)=20 Hz, CH₂CHF), 29.2, 26.1, 25.7, 22.6, 14.0.

¹⁹F NMR (186 MHz, CDCl₃) δ=−199.8 (m, CHF).

2-Fluoro-5-(4-(hexyloxy)phenyl)-1-(thiazol-2-yl)pentan-1-ol (40)Procedure A

C₂₀H₂₈FNO₂S

MW: 365.51.

Yellow oil. Yield 38%.

¹H NMR (200 MHz, CDCl₃) δ=7.90 (d, 1/7H, J=3.2 Hz, ArH), 7.83 (d, 6/7H,J=3.2 Hz, ArH), 7.45 (d, 1/7H, J=3.2 Hz, ArH), 7.35 (d, 6/7H, J=3.2 Hz,ArH), 7.05 (d, 2H, J=8.6 Hz, CH, Ph), 6.80 (d, 2H, J=8.6 Hz, CH, Ph),5.15 (dd, 1H, J_(H-H)=4.6 Hz, J_(H-F)=12.8 Hz, CHOH), 4.99-4.65 (dm, 1H,J_(H-F)=48.2 Hz, CHF), 3.93 (t, 2H, J=6.4 Hz, CH₂OPh), 2.56 (t, 2H,J=7.2 Hz, PhCH₂), 1.88-1.27 (m, 12H, 6×CH₂), 0.91 (t, 3H, J=6.8 Hz,CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=170.2, 157.2, 142.1, 133.7, 129.1, 119.7,114.3, 95.1 (d, J_(C-F)=174 Hz, CF), 73.0 (d, 1/3C, J_(C-C-F)=21 Hz,COH), 72.9 (d, 2/3C, J_(C-C-F)=24 Hz, COH), 67.9, 34.5, 31.5, 30.4 (d,J_(C-C-F)=20 Hz, CH₂), 29.2, 26.9, 25.7, 22.5, 14.0.

¹⁹F NMR (186 MHz, CDCl₃) δ=−190.0 (m, CHF), −194.4 (m, CHF).

MS (ESI) m/z (%): 366 [M+H, 100]⁺.

2-Fluoro-5-(4-(hexyloxy)phenyl)-1-(thiazol-2-yl)pentan-1-one (41)Procedure B

C₂₀H₂₆FNO₂S

MW: 363.49.

Colorless oil. Yield 60%.

¹H NMR (200 MHz, CDCl₃) δ=8.04 (d, 1H, J=2.8 Hz, ArH), 7.75 (d, 1H,J=3.0 Hz, ArH), 7.07 (d, 2H, J=8.4 Hz, CH, Ph), 6.80 (d, 2H, J=8.6 Hz,CH, Ph), 5.98 (ddd, 1H, J_(H-F)=49.6 Hz, J_(H-H)=7.6 Hz, J_(H-H)=3.6 Hz,CHF), 3.92 (t, 2H, J=6.6 Hz, CH₂OPh), 2.75-2.52 (m, 2H, PhCH₂),2.30-1.70 (m, 6H, 3×CH₂), 1.59-1.26 (m, 6H, 3×CH₂), 0.91 (t, 3H, J=6.6Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=188.9 (d, J_(C-C-F)=19 Hz, CO), 163.8, 157.4,145.1, 133.3, 129.2, 126.9, 114.4, 92.3 (d, J_(C-F)=182 Hz, CF), 68.0,34.3, 32.0 (d, J_(C-C-F)=21 Hz, CH₂CHF), 31.6, 29.3, 26.6, 25.7, 22.6,14.0.

¹⁹F NMR (186 MHz, CDCl₃) δ=−196.2 (m, CHF).

MS (ESI) m/z (%): 364 [M+H, 100]⁺.

The following new target compounds are therefore synthesised

TABLE 1 2-Oxo-thiazoles. Corres Number No. Structure MW ClogP GK146 3a

323.54 8.1 GK147 3b

245.34 3.7 GK149 3d

371.58 8.3 GK150 9 

317.45 5.4 GK151 15a

395.60 8.3 GK152 15b

317.40 3.8 GK153 19 

345.50 6.3 GK154 24 

359.53 7.1 GK155 29 

341.53 7.8 GK156 41 

363.49 6.0

A series of further compounds have been synthesised based on theprinciples outlined above. These are listed in table 2

TABLE 2 GK148

GK157

GK158

GK159

GK160

GK162

GK179

GK180

GK181

GK182

GK183

GK184

GK198

GK199

GK201

GK202

GK203

GK204

Synthetic Schemes

Characterization Data

The following target compounds of the invention are synthesisedaccording to the protocols above:

N-methoxy-N-methyloleamide (4c) Prepared by Procedure C

C₂₀H₃₉NO₂

MW: 325.53

Colorless oil. Yield 86% (985 mg).

¹H NMR (200 MHz, CDCl₃) δ=5.34-5.29 (m, 2H, CH═CH), 3.65 (s, 3H, OMe),3.15 (s, 3H, NMe), 2.38 (t, 2H, J=7.4 Hz, CH₂CO), 1.99 (m, 4H,CH₂CH═CHCH₂), 1.60 (m, 2H, CH₂CH₂CO), 1.29-1.24 (m, 20H, 10×CH₂), 0.85(t, 3H, J=5.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=174.5, 129.8, 129.6, 61.0, 31.8, 29.6, 29.6,29.4, 29.3, 29.2, 27.0, 25.5, 24.5, 22.5, 14.0.

N-methoxy-N-methyl-5-(naphthalen-2-yl)pentanamide (4e) Prepared byProcedure C

C₁₇H₂₁NO₂

MW: 271.35

Colorless oil. Yield 75% (310 mg).

¹H NMR (CDCl₃): δ=7.90-7.30 (m, 7H, ArH), 3.65 (s, 3H, OMe), 3.18 (s,3H, NMe), 2.82 (t, 2H, J=7.2 Hz, CH₂), 2.47 (t, 2H, J=7.0 Hz, CH₂),1.98-1.60 (m, 4H, 2×CH₂).

MS (ESI) m/z (%): 272 [M+H, 100]⁺.

(Z)-1-morpholinooctadec-9-en-1-one (5c) Prepared by Procedure D

C₂₂H₄₁NO₂

MW: 351.57

Colorless oil. Yield 98% (1.59 g).

¹H NMR (200 MHz, CDCl₃) δ=5.31-5.25 (m, 2H, CH═CH), 3.62-3.57 (m, 6H,CH₂OCH₂, CHHNCHH), 3.40 (t, 2H, J=5.0 Hz, CHHNCHH), 2.25 (t, 2H, J=7.4Hz, CH₂CO), 1.97-1.93 (m, 4H, CH₂CH═CHCH₂), 1.60-1.53 (m, 2H, CH₂CH₂CO),1.26-1.21 (m, 20H, 10×CH₂), 0.82 (t, 3H, J=6.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=171.6, 129.8, 129.5, 66.8, 66.5, 45.8, 41.7,32.9, 31.7, 29.6, 29.5, 29.3, 29.2, 29.1, 28.9, 27.0, 25.0, 22.5, 13.9.

(Z)-1-(Thiazol-2-yl)octadec-9-en-1-one (3c) Prepared by Procedure E

Yield when the Weinreb amide was used: 70%

Yield when the morpholine amide was used: 70%

5-(Naphthalen-2-yl)-1-(thiazol-2-yl)pentan-1-one (3e) Prepared byProcedure E

C₁₈H₁₇NOS

MW: 295.40

Yellow solid. Yield 70%

¹H NMR (200 MHz, CDCl₃) δ=7.97 (d, 1H, J=3.0 Hz, ArH), 7.80-7.75 (m, 3H,ArH), 7.75-7.63 (m, 2H, ArH), 7.50-7.30 (m, 3H, ArH), 3.21 (t, 2H, J=7.0Hz, CH₂), 2.83 (t, 2H, J=6.8 Hz, CH₂), 1.98-1.80 (m, 4H, 2×CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=193.8, 167.1, 144.6, 139.6, 133.5, 131.9,127.8, 127.5, 127.4, 127.3, 126.3, 126.1, 125.8, 125.0, 38.2, 35.7,30.8, 23.6.

MS (ESI) m/z (%): 296 [M+H, 100]⁺.

1-(Benzo[d]thiazol-2-yl)hexadecan-1-one (6a) Prepared by Procedure E

C₂₃H₃₅NOS

MW: 373.60

Yellowish solid.

Yield via Weinreb amide 60% (140 mg).

Yield via morpholine amide 85% (180 mg).

m.p.: 74-76° C.

¹H NMR (200 MHz, CDCl₃) δ=8.19 (d, 1H, J=7.4 Hz, benzothiazole), 7.98(d, 1H, J=7.4 Hz, benzothiazole), 7.62-7.49 (m, 2H, benzothiazole), 3.27(t, 2H, J=7.2 Hz, CH₂CO), 1.86-1.74 (m, 2H, CH₂CH₂CO), 1.44-1.21 (m,24H, 12×CH₂), 0.88 (t, 3H, J=6.0 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=195.6, 166.6, 153.5, 137.2, 127.5, 126.8,125.3, 122.4, 38.5, 31.9, 29.6, 29.6, 29.4, 29.3, 29.3, 29.1, 23.9,22.6, 14.1.

MS (ESI) m/z (%): 374 [M+H, 100]⁺.

1-(Benzo[d]thiazol-2-yl)-5-phenylpentan-1-one (6b) Prepared by ProcedureE

C₁₈H₁₇NOS

MW: 295.40

Yellow solid.

Yield via Weinreb amide 77% (204 mg).

Yield via morpholine amide 72% (126 mg).

m.p.: 66-68° C.

¹H NMR (200 MHz, CDCl₃) δ=8.19 (d, 1H, J=7.4 Hz, benzothiazole), 7.96(d, 1H, J=7.6 Hz, benzothiazole), 7.61-7.47 (m, 2H, benzothiazole),7.34-7.15 (m, 5H, Ph), 3.31 (t, 2H, J=6.8 Hz, CH₂CO), 2.70 (t, 2H, J=7.4Hz, PhCH₂), 1.96-1.69 (m, 4H, 2×CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=195.2, 166.3, 153.4, 142.0, 137.1, 128.3,128.2, 127.5, 126.8, 125.6, 125.2, 122.3, 38.2, 35.5, 30.8, 23.4.

MS (ESI) m/z (%): 296 [M+H, 100]⁺.

(Z)-1-(Benzo[d]thiazol-2-yl)octadec-9-en-1-one (6c) Prepared byProcedure E

C₂₅H₃₇NOS

MW: 399.63

Yellow oil.

Yield via Weinreb amide 70% (170 mg).

¹H NMR (200 MHz, CDCl₃) δ=8.17 (d, 1H, J=7.0 Hz, benzothiazole), 7.95(d, 1H, J=6.2 Hz, benzothiazole), 7.60-7.45 (m, 2H, benzothiazole),5.42-5.27 (m, 2H, CH═CH), 3.26 (t, 2H, J=7.4 Hz, CH₂CO), 2.02-2.00 (m,4H, CH₂CH═CHCH₂), 1.88-1.73 (m, 2H, CH₂CH₂CO), 1.43-1.25 (m, 20H,10×CH₂), 0.87 (t, 3H, J=6.4 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ=195.4, 166.5, 153.4, 137.1, 129.9, 129.6,127.4, 126.8, 125.2, 122.3, 38.5, 31.8, 29.7, 29.6, 29.4, 29.2, 29.2,29.1, 29.0, 27.1, 27.1, 23.8, 22.6, 14.0.

MS (ESI) m/z (%): 400 [M+H, 100]⁺.

1-(Benzo[d]thiazol-2-yl)-5-(naphthalen-2-yl)pentan-1-one (6e) Preparedby Procedure E

C₂₂H₁₉NOS

MW: 345.46

Yellow solid. Yield 72%.

¹H NMR (200 MHz, CDCl₃) δ=8.20 (d, 1H, J=6.0 Hz, ArH), 7.97 (d, 1H,J=8.0 Hz, ArH), 7.90-7.70 (m, 3H, ArH), 7.70-7.30 (m, 6H, ArH), 3.35 (t,2H, J=7.0 Hz, CH₂), 2.90 (t, 2H, J=6.8 Hz, CH₂), 2.05-1.82 (m, 4H,2×CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=195.3, 166.4, 153.5, 139.6, 137.2, 133.5,131.9, 127.8, 127.6, 127.5, 127.4, 127.3, 126.9, 126.4, 125.8, 125.3,125.0, 122.4, 38.3, 35.8, 30.7, 23.6.

MS (ESI) m/z (%): 246 [M+H, 100]⁺.

Ethyl 2-(2-(1-hydroxyhexadecyl)thiazol-4-yl)acetate (14c) Prepared byProcedure K

C₂₃H₄₁NO₃S

MW: 411.64

White solid.

¹H NMR (300 MHz, CDCl₃): δ=7.15 (s, 1H, SCH), 4.97 (dd, J₁=7.8 Hz,J₂=4.5 Hz, 1H, CHOH), 4.20 (q, J=7.2 Hz, 2H, COOCH₂), 3.82 (s, 2H,CH₂COO), 2.07-1.78 (m, 2H CH₂), 1.59-1.20 (m, 29H, 13×CH₂, CH₃), 0.89(t, J=6.3 Hz, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃): δ=174.98, 170.36, 148.18, 115.97, 71.95, 61.08,38.32, 36.93, 31.91, 29.68, 29.66, 29.56, 29.49, 29.36, 25.20, 22.69,14.14.

MS (ESI) m/z (%): 412 [M+H, 100]⁺.

Ethyl 2-(2-(1-hydroxy-5-phenylpentyl)thiazol-4-yl)acetate (14d) Preparedby Procedure K

C₁₈H₂₃NO₃S

MW: 333.45

Pale yellow solid; Yield 44%.

m.p. 53-55° C.

¹H NMR (200 MHz, CDCl₃): δ 7.35-7.07 (m, 6H, SCH, Ph), 4.93 (dd, J₁=7.8Hz, J₂=4.8 Hz, 1H, CHOH), 4.18 (q, J=7.0 Hz, COOCH₂), 3.79 (s, 2H,CH₂COO), 2.61 (t, J=7.2 Hz, CH₂Ph), 2.06-1.37 (m, 6H, 3×CH₂), 1.26 (t,J=7.2 Hz, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃) δ 174.95, 170.37, 148.20, 142.38, 128.34,128.24, 125.65, 116.00, 71.80, 61.08, 38.12, 36.90, 35.74, 31.19, 24.89,14.15.

MS (ESI) m/z (%): 334 [M+H, 100]⁺.

Ethyl 2-(2-palmitoylthiazol-4-yl)acetate (15c) Prepared by Procedure B

C₂₃H₃₉NO₃S

MW: 409.63

White solid. Yield 90%.

m.p. 46-48° C.

¹H NMR (300 MHz, CDCl₃): δ=7.54 (s, 1H, SCH), 4.21 (q, J=7.2 Hz, 2H,COOCH₂)), 3.90 (s, 2H, CH₂COO), 3.12 (t, J=7.5 Hz, 2H, CH₂CO), 1.82-1.62(m, 2H CH₂), 1.55-1.19 (m, 27H, 12×CH₂, CH₃), 0.88 (t, J=7.0 Hz, 3H,CH₃).

¹³C NMR (50 MHz, CDCl₃): δ=194.09, 170.00, 166.52, 150.95, 123.56,61.24, 38.43, 37.00, 31.91, 29.65, 29.47, 29.39, 29.35, 29.18, 23.91,22.68, 14.13.

MS (ESI) m/z (%): 410 [M+H, 100]⁺.

Ethyl 2-(2-(5-phenylpentanoyl)thiazol-4-yl)acetate (15d) Prepared byProcedure B

C₁₈H₂₁NO₃S

MW: 331.43

White oil. Yield 81%.

¹H NMR (300 MHz, CDCl₃): δ=7.55 (s, 1H, SCH), 7.34-7.16 (m, 5H, Ph),4.22 (q, J=7.2 Hz, 2H, COOCH₂), 3.91 (s, 2H, CH₂COO), 3.17 (t, J=7.5 Hz,2H, CH₂CO), 2.68 (t, J=7.2 Hz, 2H, CH₂Ph), 1.85-1.63 (m, 4H 2×CH₂), 1.30(t, J=7.2 Hz, 3H, CH₃).

¹³C NMR (50 MHz, CDCl₃): δ=193.82, 169.99, 166.42, 150.99, 142.17,128.39, 128.27, 125.71, 123.69, 61.26, 38.17, 36.99, 35.65, 30.92,23.56, 14.16.

MS (ESI) m/z (%): 332 [M+H, 99]⁺.

Ethyl 2-(2-(5-(biphenyl-4-yl)pentanoyl)thiazol-4-yl)acetate (15e)Prepared by Procedure B

C₂₄H₂₅NO₃S

MW: 407.53

White solid.

¹H NMR (200 MHz, CDCl₃): δ=7.65-7.18 (m, 10H, Ar, SCH), 4.21 (q, J=7.4Hz, 2H, COOCH₂), 3.90 (s, 2H, CH₂COO), 3.18 (t, J=6.6 Hz, CH₂CO), 2.70(t, J=7.2 Hz, CH₂Ph), 1.94-1.65 (m, 4H, 2×CH₂), 1.28 (t, J=7.2 Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃): δ=193.79, 169.95, 166.40, 151.01, 141.29,141.06, 138.66, 128.80, 128.66, 127.01, 126.95, 123.67, 61.22, 38.15,36.97, 35.25, 30.85, 23.57, 14.14.

MS (ESI) m/z (%): 408 [M+H, 100]⁺.

2-palmitoylthiazole-4-carboxylic acid (15′ a) Prepared by Procedures L,then B

C₂₀H₃₃NO₃S

MW: 367.55

White solid. Yield 50%.

m.p. 98-100° C.

¹H NMR (200 MHz, CDCl₃): δ=8.39 (s, 1H, CH), 3.25-3.00 (m, 2H, CH₂),1.80-1.55 (m, 2H, CH₂), 1.40-1.00 (m, 24H, 12×CH₂), 0.88 (t, 3H, J=6.8Hz, CH₃).

¹³C NMR (50 MHz, CDCl₃+CD₃OD): δ=193.9, 166.4, 164.6, 151.5, 131.8,37.9, 31.5, 29.2, 29.0, 28.9, 28.7, 23.2, 22.2, 13.4.

MS (ESI) m/z (%): 366 [M−H, 100]-.

2-(5-Phenylpentanoyl)thiazole-4-carboxylic acid (15′b) Prepared byProcedure M

C₁₅H₁₅NO₃S

MW: 289.35

White solid. Yield 86% (25 mg).

¹H NMR (CDCl₃): δ=8.55 (s, 2H, ArH, COOH), 7.30-7.10 (m, 5H, Ph), 3.26(t, 2H, J=6.8 Hz, CH₂), 2.66 (t, 2H, J=7.0 Hz, CH₂), 1.90-1.63 (m, 4H,2×CH₂).

¹³C NMR (CDCl₃): δ=193.5, 167.8, 164.6, 147.4, 142.0, 134.9, 128.4,128.3, 125.8, 38.2, 35.6, 30.7, 23.2.

MS (ESI) m/z (%): 290 [M+H, 47]⁺.

2-(2-Palmitoylthiazol-4-yl)acetic acid (15′c) Prepared by Procedures L,then B

C₂₁H₃₅NO₃S

MW: 381.57

White solid.

¹H NMR (300 MHz, CDCl₃): δ 7.55 (s, 1H, SCH), 3.98 (s, 2H, CH₂COO), 3.13(t, J=7.6 Hz, 2H, CH₂CO), 1.82-1.69 (m, 2H, CH₂), 1.43-1.18 (m, 24H,12×CH₂), 0.89 (t, J=6.9 Hz, 3H, CH₃).

MS (ESI) m/z (%): 336 [M-COOH—H, 100]⁻, 380 [M−H, 46]⁻.

2-(2-(5-Phenylpentanoyl)thiazol-4-yl)acetic acid (15′ d) Prepared byProcedure M

C₁₆H₁₇NO₃S

MW: 303.38

White oil. Yield 89%.

¹H NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H, SCH), 7.35-7.08 (m, 5H, Ph),3.88 (s, 2H, CH₂COO), 3.11 (t, J=7.5 Hz, 2H, CH₂CO), 2.63 (t, J=7.0 Hz,2H, CH₂Ph), 1.85-1.63 (m, 4H 2×CH₂).

MS (ESI) m/z (%): 304 [M+H, 77]⁺.

(S)-tert-Butyl4-(benzyloxycarbonylamino)-5-(methoxy(methyl)amino)-5-oxopentanoate(43b) Prepared by Procedure C

C₁₉H₂₈N₂O₆

MW: 380.44

Colorless oil. Yield 100%.

¹H NMR (200 MHz, CDCl₃) δ=7.35-7.20 (m, 5H, ArH), 5.67 (d, 1H, J=8.0 Hz,NH), 5.06 (s, 2H, CH₂), 4.80-4.60 (m, 1H, CH), 3.73 (s, 3H, OMe), 3.15(s, 3H, NMe), 2.40-1.70 (m, 4H, CH₂), 1.38 (s, 9H, ^(t)Bu).

¹³C NMR (50 MHz, CDCl₃) δ=171.9, 155.9, 136.1, 128.3, 127.9, 127.8,80.3, 66.6, 61.4, 50.3, 31.9, 31.0, 27.9, 27.4.

MS (ESI) m/z (%): 381 [M+H, 100]⁺.

(S)-tert-Butyl5-(methoxy(methyl)amino)-5-oxo-4-(2-phenylacetamido)pentanoate (45b)Prepared by Procedures V, then W

C₁₉H₂₈N₂O₅

MW: 364.44

Colorless oil.

¹H NMR (200 MHz, CDCl₃) δ=7.40-7.20 (m, 5H, ArH), 6.38 (d, 1H, J=8.0 Hz,NH), 5.02-4.90 (m, 1H, CH), 3.65 (s, 3H, OMe), 3.55 (s, 2H, CH₂), 3.18(s, 3H, NMe), 2.25-1.70 (m, 4H, CH₂), 1.40 (s, 9H, ^(t)Bu).

¹³C NMR (50 MHz, CDCl₃) δ=172.1, 170.9, 166.3, 134.6, 129.3, 128.9,127.2, 80.5, 61.6, 48.7, 43.6, 31.1, 28.0, 27.2.

MS (ESI) m/z (%): 365 [M+H, 100]⁺.

N-(2-(Benzo[d]thiazol-2-yl)-2-oxoethyl)-2-phenylacetamide (46a) Preparedby Procedure E

C₁₇H₁₄N₂O₂S

MW: 310.37

Orange solid.

¹H NMR (200 MHz, CDCl₃) δ=8.11 (d, 1H, J=8.0 Hz, ArH), 7.94 (d, 1H,J=8.0 Hz, ArH), 7.65-7.40 (m, 2H, ArH), 7.39-7.20 (m, 5H, ArH), 6.34 (b,1H, NH), 4.95 (d, 2H, J=5.2 Hz, CH₂), 3.67 (s, 2H, CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=189.7, 171.4, 163.1, 153.3, 136.9, 134.4,129.5, 129.0, 128.1, 127.4, 127.1, 125.6, 122.3, 46.8, 43.5.

MS (ESI) m/z (%): 311 [M+H, 100]⁺.

(S)-tert-Butyl5-(benzo[d]thiazol-2-yl)-5-oxo-4-(2-phenylacetamido)pentanoate (46b)Prepared by Procedure E

C₂₄H₂₆N₂O₄S

MW: 438.54

Colorless Oil. Yield 50%.

¹H NMR (200 MHz, CDCl₃) δ=8.10 (d, 1H, J=8.0 Hz, ArH), 7.91 (d, 1H,J=8.0 Hz, ArH), 7.62-7.20 (m, 7H, ArH), 6.77 (d, 1H, J=8.0 Hz, NH),5.68-5.70 (m, 1H, CH), 3.61 (s, 2H, CH₂), 2.50-1.98 (m, 4H, CH₂), 1.38(s, 9H, ^(t)Bu).

¹³C NMR (50 MHz, CDCl₃) δ=192.5, 172.1, 170.9, 163.5, 153.2, 137.0,134.4, 129.3, 128.8, 127.9, 127.2, 127.0, 125.8, 122.2, 80.7, 55.1,43.4, 30.3, 30.6, 27.9, 27.3.

MS (ESI) m/z (%): 439 [M+H, 55]⁺.

(S)-5-(Benzo[d]thiazol-2-yl)-5-oxo-4-(2-phenylacetamido)pentanoic acid(47) Prepared by Procedure X

C₂₀H₁₈N₂O₄S

MW: 382.43

Yellow solid. Yield 50%.

¹H NMR (200 MHz, CDCl₃) δ=8.11 (d, 1H, J=8.0 Hz, ArH), 7.94 (d, 1H,J=8.0 Hz, ArH), 7.65-7.40 (m, 2H, ArH), 7.38-7.10 (m, 5H, ArH), 6.71 (d,1H, T=8.0 Hz, NH), 5.90-5.60 (m, 1H, CH), 3.63 (s, 2H, CH₂), 2.55-2.25(m, 3H, CH₂), 2.20-1.90 (m, 1H, CH₂).

¹³C NMR (50 MHz, CDCl₃) δ=192.3, 177.0, 171.6, 163.3, 153.3, 137.1,134.2, 129.4, 129.0, 128.2, 127.5, 127.2, 126.1, 125.8, 122.3, 55.2,43.5, 30.1, 27.5.

MS (ESI) m/z (%): 381 [M−H, 100]⁻.

Some of the compounds above were tested using an in vitro cPLA₂ enzymeactivity assay.

In Vitro cPLA2 Assay

Assay for cPLA2 activity was performed by the use of sonicated vesiclesof 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphorylcholine (100 μM)containing 100,000 cpm of 1-palmitoyl-2-[114C]arachidonoylsn-glycerol-3-phosphorylcholine in 100 mM Hepes, pH 7.5,80 μM Ca2, 2 mM dithiothreitol, and 0.1 mg/ml BSA as described.Following a 35-mM incubation at 37° C., the reaction was terminated(derived from Wijkander et al). The lower phase was separated by thinlayer chromatography, and the spot corresponding to free[1-14C]arachidonic acid was visualized by digital imaging and quantifiedwith a PhosphorImager (Fuji Instruments). The source of cPLA₂ enzyme wasrecombinant overexpression of the human gene for group IVa PLA2 inbaculovirus insect cell expression system, as described in Abdullah etal.

-   Wijkander, J., and Sundler, R. (1991) Eur. J. Biochem. 202, 873-880-   Abdullah, K., et al. (1995) Human cytosolic phospholipase A2    expressed in insect cells is extensively phosphorylated on Ser-505.    Biochim Biophys Acta. 1995 May 11; 1244(1):157-64.

The results are presented below:

Compound No. Enzyme Assay IC 50 3b 3050 nM 24 3650 nM 41 3700 nM

Further Testing was Carried Out as Follows: Reagents

The Cell Culture SW982 model cell line at a confluent or spheroid state(Wada Y, 2005) was used since gene expression and generation ofproinflammatory cytokines resemble RA-derived synovial fibroblast-likecells.

AA release assay: 1 h preincubation at 50 and 25 μM—4h IL-1Bstimulation, repeated 2-3 times. Only inhibitors that showed a ˜50%inhibition in either of the initial two concentrations were furthertested in a dose-response. IC50 is evaluated from dose-responseinhibitions curves.

PGE2 analysisPGE₂ detection

Samples and controls were slowly thawed and diluted (between 1:1 and1:2500) in the standard diluent. The maximal dilution was 1:10 for onestep. That is why several intermediate dilutions were prepared. In thebeginning all values were determined from duplicates. After havingminimized technical errors, samples were only analyzed as individuals.All further steps, except for some minor corrections, were performedaccording to the manufacturer's recommendations as can be found in themanual of the EIA kit. In order to optimize the results, the incubationtime of the alkaline phosphatase substrate was prolonged by 15 minutes.During the incubation, the plates were kept in the dark. An example ofthe arrangements of the samples and controls is illustrated in theappendix. The read-out was carried out with a Multiscan plate reader(Ascent Labsystems) at wavelengths of 414 and 595 nm after 10 secondsshaking at 120 rpm. The corresponding software to obtain the data wasthe Ascent software for Multiscan, Version 2.4.1.

Data were processed using Microsoft Office Excel 2003 and SigmaPlot10.0.

AA release cPLA2 SW982 in vitro cells assay IC50 IC50 PGE2-assay CodeStructure (μM) (μM) % inhibition GK150

5.8 Not yet known GK152

7.4 (2 h) >25 (4 h) >5 0.1 uM: 41% 3 uM:: 38% 10 uM:: 30% 30 uM: 31%GK159

<2 (2 h) ~25 (4 h) >5 0.3 uM:: 76% 3 uM: 18% 10 uM: 23% 30 uM: 10% GK160

4.9 7.2 10 uM: 12% 30 uM: 30% GK181

1.4 10 uM: 16.3% 30 uM: 22.5% GK185

2.8 2 Not yet known

Other Embodiments

From the foregoing description, it will be apparent that variations andmodifications may be made to the invention described herein to adopt itto various usages and conditions. Such embodiments are also within thescope of the following claims.

The recitation of a listing of elements in any definition of a variableherein includes definitions of that variable as any single element orcombination (or subcombination) of listed elements. The recitation of anembodiment herein includes that embodiment as any single embodiment orin combination with any other embodiments or portions thereof.

All patents and publications mentioned in this specification are hereinincorporated by reference to the same extent as if each independentpatent and publication was specifically and individually indicated to beincorporated by reference.

1. A compound of formula (I′)

wherein X is O or S; R₁ is H, OH, SH, nitro, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, halo, haloC₁₋₆alkyl, CN, C₁₋₆-alkyl, OC₁₋₆alkyl,C₂₋₆-alkenyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, C₁₋₆alkylC₆₋₁₀aryl,heterocyclyl, heteroaryl, CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂,OCOC₁₋₆alkyl, C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl or is an acidicgroup, such as a group comprising a carboxyl, phosphate, phosphinate,sulfate, sulfonate, or tetrazolyl group; R₂ is as defined for R₁ or R₁and R₂ taken together can form a 6-membered aromatic ring optionallysubstituted by up to 4 groups R₅; each R_(3′) is the same or differentand is H, C₁₋₆alkylCOOR_(a) where R_(a) is H or C₁₋₆ alkyl, halo(preferably fluoro), or CHal₃ (preferably CF₃), each R₅ is defined asfor R₁; V_(1′) is a covalent bond, —NHCOC₀₋₆alkyl- (i.e. where NH isadjacent the CR₃, group), a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiplyunsaturated alkenyl group; said alkyl or alkenyl groups being optionallyinterupted by one or more heteroatoms selected from O, NH, N(C₁₋₆alkyl), S, SO, or SO₂; M₁ is absent or is a C₅₋₁₀ cyclic group or aC₅₋₁₅ aromatic group (e.g. C₆₋₁₄ aromatic group); and R₄ is H, halo, OH,CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, haloC₁₋₆alkyl, a C₁₋₂₀alkylgroup, or C₂₋₂₀-mono or multiply unsaturated alkenyl group, saidC₁₋₂₀alkyl or C₂₋₂₀alkenyl groups being optionally interupted by one ormore heteroatoms selected from O, NH, N(C₁₋₆ alkyl), S, SO, or SO₂; withthe proviso that the group V_(1′)M₁R₄ as a whole provides at least 4backbone atoms from the C(R_(3′)) group; or a salt, ester, solvate,N-oxide, or prodrug thereof with the proviso that R₄M₁V_(1′)C(R_(3′))₂is not oleyl.
 2. A compound as claimed in claim 1 of formula (II)

wherein R₁, R₂, R₃, R₅ and R₄M₁V₁ are as hereinbefore defined; or asalt, ester, solvate, N-oxide, or prodrug thereof; with the proviso thatR₄M₁V₁C(R₃) is not oleyl.
 3. A compound of formula (III)

wherein R₆ is H, C₁₋₆alkyl, COOH, COOC₁₋₆alkyl, CONH₂, CONHC₁₋₆alkyl,CON(C₁₋₆alkyl)₂, C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl; R₇ is H; whereinR₃ is as hereinbefore defined; V₁ is a covalent bond or a C₁₋₂₀alkylgroup, or C₂₋₂₀-mono or multiply unsaturated alkenyl group; M₁ is acovalent bond or is a C₅₋₁₀ cyclic group or a C₅₋₁₀ aromatic group; andR₄ is H, halo, OH, CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,haloC₁₋₆alkyl, a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturatedalkenyl group, said alkyl or alkenyl groups being optionally interuptedby one or more heteroatoms selected from O, NH, N(C₁₋₆ alkyl), S, SO, orSO₂; or a salt, ester, solvate, N-oxide, or prodrug thereof with theproviso that R₄M₁V₁C(R₃) is not oleyl or —(CH₂)₆Ph.
 4. A compound asclaimed in claim 1 in which X is S.
 5. A compound as claimed in claim 1in which R₁ is hydrogen.
 6. A compound as claimed in claim 1 in which R₂is COOH, COOC₁₋₆alkyl and C₁₋₆alkylCOOH.
 7. A compound as claimed inclaim 1 in which R₁ and R₂ can be taken together to form a ring systemsuch as a phenyl ring or pyridine ring optionally substituted by 1 or 2groups R₅.
 8. A compound as claimed in claim 1 in which each R_(3′) orR₃ is hydrogen or halo, especially fluoro.
 9. A compound as claimed inclaim 1 in which V₁M₁R₄ or V_(1′)M₁R₄ provides at least 10 backboneatoms from the C(R₃) or C(R_(3′)) group.
 10. A compound as claimed inclaim 1 in which V₁ or V_(1′) is preferably a C₁₋₁₅-alkyl group,C₂₋₂₀-alkenyl group or is a —C₁₋₆alkylO-group (i.e. where the O atombonds to M₁).
 11. A compound as claimed in claim 1 in which M₁ is eitherabsent or is an C₆₋₁₀aryl group, especially a phenyl group.
 12. Acompound as claimed in claim 1 in which R₄ is an H atom, C₁₋₁₀alkylgroup or an C₁₋₁₀alkoxy group.
 13. A compound as claimed in claim 1being

or a salt, ester, solvate, N-oxide, or prodrug thereof
 14. Apharmaceutical composition comprising a compound of formula (I′), (II)or (III) as claimed in claim
 1. 15. A method of treating a chronicinflammatory disorder comprising administering to a patient in needthereof an effective amount of a compound of formula (I′).

wherein X is O or S; R₁ is H, OH, SH, nitro, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, halo, haloC₁₋₆alkyl, CN, C₁₋₆-alkyl, OC₁₋₆alkyl,C₂₋₆-alkenyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, C₁₋₆alkylC₆₋₁₀aryl,heterocyclyl, heteroaryl, CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂,OCOC₁₋₆alkyl, C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl or is an acidicgroup, such as a group comprising a carboxyl, phosphate, phosphinate,sulfate, sulfonate, or tetrazolyl group; R₂ is as defined for R₁ or R₁and R₂ taken together can form a 6-membered aromatic ring optionallysubstituted by up to 4 groups R₅; each R_(3′) is the same or differentand is H, C₁₋₆alkylCOOR_(a) where R_(a) is H or C₁₋₆ alkyl, halo(preferably fluoro), or CHal₃ (preferably CF₃), each R₅ is defined asfor R₁; V_(1′) is a covalent bond, —NHCOC₀₋₆alkyl- (i.e. where NH isadjacent the CR_(3′) group), a C₁₋₂₀alkyl group, or C₂₋₂₀-mono ormultiply unsaturated alkenyl group; said alkyl or alkenyl groups beingoptionally interupted by one or more heteroatoms selected from O, NH,N(C₁₋₆ alkyl), S, SO, or SO₂; M₁ is absent or is a C₅₋₁₀ cyclic group ora C₅₋₁₅ aromatic group (e.g. C₆₋₁₄ aromatic group); and R₄ is H, halo,OH, CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, haloC₁₋₆alkyl, aC₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturated alkenyl group,said C₁₋₂₀alkyl or C₂₋₂₀alkenyl groups being optionally interupted byone or more heteroatoms selected from O, NH, N(C₁₋₆ alkyl), S, SO, orSO₂; with the proviso that the group V_(1′)M₁R₄ as a whole provides atleast 4 backbone atoms from the C(R_(3′))₂ group; or a salt, ester,solvate, N-oxide, or prodrug thereof for use in the treatment of achronic inflammatory condition.
 16. A method as claimed in claim 15comprising administration of a compound of formula (I)

wherein X is O or S; R₁ is H, OH, SH, nitro, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, halo, haloC₁₋₆alkyl, CN, C₁₋₆-alkyl, OC₁₋₆alkyl,C₁₋₆alkylCOOH, C₁₋₆alkylCOOC₁₋₆alkyl, C₂₋₆-alkenyl, C₃₋₁₀cycloalkyl,C₆₋₁₀aryl, C₁₋₆alkylC₆₋₁₀aryl, heterocyclyl, heteroaryl, CONH₂,CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, OCOC₁₋₆alkyl, or is an acidic group,such as a group comprising a carboxyl, phosphate, phosphinate, sulfate,sulfonate, or tetrazolyl group; R₂ is as defined for R₁ or R₁ and R₂taken together can form a 6-membered aromatic ring optionallysubstituted by up to 4 groups R₅; R₃ is H, halo (preferably fluoro), orCHal₃ (preferably CF₃), each R₅ is defined as for R₁; V₁ is a covalentbond or a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturatedalkenyl group; said alkyl or alkenyl groups being optionally interuptedby one or more heteroatoms selected from O, NH, N(C₁₋₆ alkyl), S, SO, orSO₂; M₁ is absent or is a C₅₋₁₀ cyclic group or a C₅₋₁₅ aromatic group;and R₄ is H, halo, OH, CN, nitro, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,haloC₁₋₆alkyl, a C₁₋₂₀alkyl group, or C₂₋₂₀-mono or multiply unsaturatedalkenyl group, said C₁₋₂₀alkyl or C₂₋₂₀alkenyl groups being optionallyinterupted by one or more heteroatoms selected from O, NH, N(C₁₋₆alkyl), S, SO, or SO₂; with the proviso that the group V₁M₁R₄ as a wholeprovides at least 4 backbone atoms from the C(R₃) group; or a salt,ester, solvate, N-oxide, or prodrug thereof.
 17. A method as claimed inclaim 15 wherein said chronic inflammatory disorder isglomerulonephritis, rheumatoid arthritis or psoriasis.
 18. A method oftreating atopic dermatitis, allergic contact dermatitis, seborrheicdermatitis, pityriasis rosea, lichen planus or drug eruptions comprisingadministering to a patient in need thereof an effective amount of acompound of formula (I′) as claimed in claims
 15. 19. A method oftreating arthritis, dermatoses, inflammatory CNS diseases, multiplesclerosis, chronic obstructive pulmonary disease, chronic lunginflammatory conditions, inflammatory bowel disease such as ulcerativecolitis and crohns disease or cardiovascular disease comprisingadministering to a patient in need thereof an effective amount of acompound of formula (I′) as claimed in claim
 15. 20. A process for theformation of a 2-oxothiazole comprising reacting a compound of formula(IV)

wherein Y is an organic group, e.g. a group R₄M₁V₁CH(R₃), with anoptionally substituted thiazole in the presence of a base so as to forman optionally substituted compound of formula (V)


21. A compound of formula (VIII)

wherein R₁, R₂, R₃, R_(3′), R₅ and R₄M₁V₁/R₄M₁V_(1′) are as hereinbeforedefined; or a salt, ester, solvate, N-oxide, or prodrug thereof.